Submissions for variant NM_000371.4(TTR):c.424G>A (p.Val142Ile)

gnomAD frequency: 0.00501  dbSNP: rs76992529

Total submissions: 42

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030575	SCV000053250	pathogenic	Amyloid Cardiomyopathy, Transthyretin-related	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000014368	SCV000060031	pathogenic	Familial amyloid neuropathy	2020-03-30	criteria provided, single submitter	clinical testing	The p.Val142Ile variant in TTR (alternate nomenclature p.Val122Ile) has been reported in >70 predominantly African American individuals with confirmed cardiac amyloidosis that presented with clinical features of cardiomyopathy or heart failure that typically presented with a later onset (after age 60-70). It is believed to be the most common variant identified, particularly amongst elderly African Americans (Jacobson 1997, Conners 2009, Lee 2011, Ruberg 2012, Arruda-Olsen 2013, Damy 2016). Individuals homozygous for the variant have been reported to have earlier onset of symptoms (Reddi 2014, Liu 2014). This variant has been shown to increase the risk for congestive heart failure in older individuals (>70 years), with two small studies reporting an age adjusted odds ratio of 1.5-2 [95% CI 1.2-2.7] (Quarta 2015, Damrauer 2019). Additionally, this variant has also been reported as a pathogenic variant by several clinical laboratories in ClinVar (Variation ID 13426). It is present in 1.6% (405/24968) of African chromosomes by gnomAD, including 3 homozygotes. Although this frequency is high in the general population, it is consistent with the age-dependent and possibly reduced penetrance of this disease. This variant has been shown to render the TTR protein complex unstable, causing misfolding and deposits in the myocardium (Jiang 2001, Askansas 2003). In summary, this variant is pathogenic for autosomal dominant late-onset transthyretin amyloidosis, though penetrance may not be complete.
GeneDx	RCV000078674	SCV000209380	pathogenic	not provided	2020-12-29	criteria provided, single submitter	clinical testing	Originated in a small number of founder carriers in southern West Africa (Jacobson et al., 2016); Reported as heterozygous or homozygous in individuals with familial amyloid cardiomyopathy and senile systemic amyloidosis (SSA); these disorders usually have an age-dependent penetrance with onset later in life (age > 50-60 years), characterized by amyloid deposits in the heart leading to congestive heart failure and conduction system disturbances (Jacobson et al., 1997a; Jacobson et al., 1997b); Reported in individuals of varying ethnic backgrounds in the Online Registry for Mutations in Hereditary Amyloidosis (Rowczenio et al., 2014); Cultured skeletal muscle fibers from patients harboring the V142I variant had vacuolar degeneration, congophilic inclusions, clusters of immunocolocalizing beta-amyloid and TTR accumulations (Askanas et al., 2003); Renders the TTR complex unstable, leading to unfolding and lower tetramer stability (Jiang et al., 2001); This variant is associated with the following publications: (PMID: 18276611, 24474780, 22083004, 24633258, 27618855, 25997029, 26537620, 29520877, 31371117, 31821430, 20301373, 15820680, 17503405, 11752443, 12874414, 9017939, 25551524, 22995991, 23713495, 23716704, 22745357, 20435197, 24184229, 22184092, 24818650, 22877808, 20981092, 26894299, 26428663, 24070600, 2349941, 27652282, 28090011, 26243339, 27364045, 25819286, 26002815, 26123279, 27386769, 26017327, 28335735, 27838833, 28635949, 28944235, 29052438, 29073801, 28870641, 29016222, 30093168, 28475415, 29764897, 30683924, 31659433, 31740141, 31554435, 32674397, 32150461, 31980526, 31589614, 32269295, 26656838, 32399692, 32376792)
Invitae	RCV000014368	SCV000284750	pathogenic	Familial amyloid neuropathy	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine with isoleucine at codon 142 of the TTR protein (p.Val142Ile). There is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs76992529, gnomAD 1.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with transthyretin amyloidosis (PMID: 12050338, 19781421, 22745357, 24184229, 25846356). It is commonly reported in individuals of African American ancestry (PMID: 20435197, 22745357, 22877808, 25846356). This variant is also known as p.Val122Ile. ClinVar contains an entry for this variant (Variation ID: 13426). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TTR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TTR function (PMID: 15820680, 17503405, 18276611). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000243161	SCV000318173	pathogenic	Cardiovascular phenotype	2022-08-22	criteria provided, single submitter	clinical testing	The p.V142I pathogenic mutation (also known as c.424G>A and V122I), located in coding exon 4 of the TTR gene, results from a G to A substitution at nucleotide position 424. The valine at codon 142 is replaced by isoleucine, an amino acid with highly similar properties. This alteration is the most common TTR mutation in individuals of African descent, having been observed in >3% of African Americans, and is associated with familial amyloidotic cardiomyopathy (Jacobson DR et al. N Engl J Med. 1997;336:466-73; Jacobson DR et al. Amyloid. 2015;22(3):171-4). This mutation has been reported to decrease the stability of the transthyretin tetramer and lower the kinetic barrier for tetramer dissociation, which increases the extent and rate of amyloid fibril formation (Jiang X et al. PNAS. 2001;98(26):14943-8). The clinical penetrance of this mutation is unknown and age-dependent; before age sixty-five, this mutation has little or no impact on cardiac function or mortality in the majority of patients, while after age seventy, heterozygotes have been reported to show a higher frequency of congestive heart failure, greater mortality, and more evidence of cardiac amyloidosis than age, gender, and ethnicity-matched controls (Buxbaum J et al. Am Heart J. 2010;159(5):864-70; Quarta CC et al. N Engl J Med. 2015;372(1):21-9). Although cardiac disease is the most commonly observed symptom of individuals with this mutation, other types of neuropathy have also been observed (Coelho T et al. Curr Med Res Opin. 2013;29(1):63-76). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Eurofins Ntd Llc (ga)	RCV000078674	SCV000331406	pathogenic	not provided	2013-05-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000014368	SCV000408397	pathogenic	Familial amyloid neuropathy	2023-03-17	criteria provided, single submitter	clinical testing	The TTR c.424G>A (p.Val142Ile) missense variant results in the substitution of valine at amino acid position at 142 with isoleucine. This variant, which is also known as p.Val122Ile, has been described as one of the most common pathogenic variants associated with hereditary transthyretin amyloidosis and is present in a heterozygous state at a frequency of approximately 3.5% in the African American population (PMID: 20301373; PMID: 26123279). The c.424G>A variant is generally associated with cardiac amyloidosis with either limited or no significant neurological involvement (PMID: 20435197; PMID: 24184229; PMID: 25551524; PMID: 26537620). However, additional phenotypes have been observed which include gait abnormalities, gastrointestinal and urinary phenotypes, muscle weakness, carpal tunnel syndrome, spinal stenosis, and neurologic features including tingling, numbness, and neuropathic pain (PMID: 25819286; PMID: 27386769; PMID: 27838833; PMID: 31135624; PMID: 33467513). Phenotype severity generally increases after the age of 60 and can include congestive heart failure (PMID: 20435197; PMID: 24184229; PMID: 25551524; PMID: 26537620). Penetrance is incomplete and variable by ethnic origin and geographic region (PMID: 20301373). While hereditary transthyretin amyloidosis is inherited in an autosomal dominant pattern, homozygous and compound heterozygous individuals are also reported: across a selection of the available literature, the c.424G>A variant is found in a homozygous state in 19 patients, in a compound heterozygous state in two patients, and in a heterozygous state in 36 patients (PMID: 2349941; PMID: 9017939; PMID: 20435197; PMID: 24073013; PMID: 24184229; PMID: 24633258; PMID: 25819286; PMID: 25551524; PMID: 26537620; PMID: 26428663). The highest frequency of this allele in the Genome Aggregation Database is 0.01654 in the African/African American population (version 3.1.2). This allele frequency is high but is consistent with disease prevalence estimates in specific populations. Functional studies showed that the variant demonstrated an altered speed of tetramer dissociation, greater formation of amyloid fibrils, and an unstable TTR tetramer compared to wild type (PMID: 11752443; PMID: 18276611). Based on the available evidence, the c.424G>A (p.Val142Ile) variant is classified as pathogenic for hereditary transthyretin amyloidosis.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000078674	SCV000605508	pathogenic	not provided	2023-11-22	criteria provided, single submitter	clinical testing	The TTR c.424G>A; p.Val142Ile variant (rs76992529), also known as Val122Ile, is one of the most common pathogenic variants associated with late-onset amyloidosis in individuals often of African American ancestry (Buxbaum 2017, Damy 2016, Jacobson 2016) and is classified as pathogenic by several sources in the ClinVar database (Variation ID: 13426). The variant does not appear to have an effect on cardiac function until after the age of 60 (Buxbaum 2010, Reddi 2014, Quarta 2015). Although this variant commonly has a predominant clinical expression of hypertrophic restrictive cardiomyopathy with mild or no neurological symptoms, it has also been reported in an individual with neurological findings and no cardiac involvement (Stancanelli 2017). Functional studies have demonstrated instability of the variant tetramer protein (Altland 2007, Jiang 2001, Sekijima 2005, Steward 2008), and suggest the variant predisposes to accumulation of amyloid beta peptide as well as causes vacuolar degeneration leading to decreased viability of cultured skeletal muscle (Askanas 2003). This variant is found in the African/African American population with an allele frequency of 1.6% (405/24,968 alleles, including 3 homozygotes) in the Genome Aggregation Database. Although the allele frequency is high, it is consistent with the disease prevalence. The valine at codon 142 is highly conserved and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.645). Based on available information, this variant is considered to be pathogenic. References: Altland K et al. Genetic microheterogeneity of human transthyretin detected by IEF. Electrophoresis. 2007 Jun;28(12):2053-64. PMID: 17503405. Askanas V et al. Transthyretin Val122Ile, accumulated Abeta, and inclusion-body myositis aspects in cultured muscle. Neurology. 2003 Jul 22;61(2):257-60. PMID: 12874414. Buxbaum J et al. Significance of the amyloidogenic transthyretin Val 122 Ile allele in African Americans in the Arteriosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies. Am Heart J. 2010 May;159(5):864-70. PMID: 20435197. Buxbaum JN et al. Transthyretin V122I (pV142I)* cardiac amyloidosis: an age-dependent autosomal dominant cardiomyopathy too common to be overlooked as a cause of significant heart disease in elderly African Americans. Genet Med. 2017 Jul;19(7):733-742. PMID: 28102864. Damy T et al. Prevalence and clinical phenotype of hereditary transthyretin amyloid cardiomyopathy in patients with increased left ventricular wall thickness. Eur Heart J. 2016 Jun 14;37(23):1826-34. PMID: 26537620. Jacobson DR et al. The prevalence and distribution of the amyloidogenic transthyretin (TTR) V122I allele in Africa. Mol Genet Genomic Med. 2016 Jul 14;4(5):548-56. PMID: 27652282. Jiang X et al. The V122I cardiomyopathy variant of transthyretin increases the velocity of rate-limiting tetramer dissociation, resulting in accelerated amyloidosis. Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):14943-8. PMID: 11752443. Reddi HV et al. Homozygosity for the V122I mutation in transthyretin is associated with earlier onset of cardiac amyloidosis in the African American population in the seventh decade of life. J Mol Diagn. 2014 Jan;16(1):68-74. PMID: 24184229. Sekijima Y et al. The biological and chemical basis for tissue-selective amyloid disease. Cell. 2005 Apr 8;121(1):73-85. PMID: 15820680. Stancanelli C et al. Phenotypic variability of TTR Val122Ile mutation: a Caucasian patient with axonal neuropathy and normal heart. Neurol Sci. 2017 Mar;38(3):525-526. PMID: 27838833. Steward RE et al. Different disease-causing mutations in transthyretin trigger the same conformational conversion. Protein Eng Des Sel. 2008 Mar;21(3):187-95. PMID: 18276611. Quarta CC et al. The amyloidogenic V122I transthyretin variant in elderly black Americans. N Engl J Med. 2015 Jan 1;372(1):21-9. PMID: 25551524.
Fulgent Genetics, Fulgent Genetics	RCV002476965	SCV000611333	pathogenic	Hyperthyroxinemia, dystransthyretinemic; Familial amyloid neuropathy; Carpal tunnel syndrome 1	2022-04-26	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000078674	SCV000616219	pathogenic	not provided	2023-01-06	criteria provided, single submitter	clinical testing	This variant is the most common variant associated with autosomal dominant TTR-related amyloid cardiomyopathy (PMID 9017939), formerly known as familial amyloidotic cardiomyopathy (FAC); therefore the frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant is also referred to as c.7356G>A (p.Val122Ile) in published literature. According to published literature, there is no reported difference in clinical presentation between individuals with this variant in the heterozygous or homozygous state (PMID: 19781421). This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments indicate this variant results in reduced tetramer and dimer stability compared to wild-type (PMID: 17503405).
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000735409	SCV000854564	pathogenic	Anemia; Pancytopenia; Bone marrow hypocellularity		criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000211747	SCV000902011	pathogenic	Cardiomyopathy	2023-05-30	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000014368	SCV000995173	pathogenic	Familial amyloid neuropathy	2019-05-20	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000853387	SCV000996263	pathogenic	ATTRV122I amyloidosis	2019-03-12	criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in patients with Transthyretin-related Amyloid Cardiomyopathy. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.15% (417/277140), including three reports of hymozygous individuals. The p.Val142Ile is found in approximately 3.5% of African Americans. In silico analyses support a deleterious effect of the c.424G>A, p.Val142Ile variant on protein function. This variant is clearly defined as a late-onset cardiac amyloidosis causative allele (PMID: 24070600, 24184229). It is a common cause of amyloidosis in individuals of African American ancestry and typically causes symptoms after the sixth decade of life (PMID: 20435197, 22877808). It has also been observed in individuals from other populations and causes the same phenotype (PMID: 25846356, 22745357). ClinVar contains an entry for this variant (Variation ID: 13426). Experimental studies have shown that this missense change weakens the stability of the TTR tetramer protein complexes (PMID: 15820680, 17503405, 18276611). Based on the available evidence, the c.424G>A, p.Val142Ile variant is classified as Pathogenic.
Mendelics	RCV000014368	SCV001140876	pathogenic	Familial amyloid neuropathy	2019-05-28	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173290	SCV001336374	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000078674	SCV001433271	pathogenic	not provided	2019-06-12	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000014368	SCV001441407	pathogenic	Familial amyloid neuropathy	2022-08-23	criteria provided, single submitter	clinical testing	The c.424G>A variant in TTR is an established pathogenic variant in individuals of African American ancestry with hereditary transthyretin (ATTR) amyloidosis related cardiomyopathy as it has been reported in 10% of African Americans older than age 65 with severe congestive heart failure [PMID: 28102864], and it has been deposited in ClinVar [ClinVar ID: 13426] as Pathogenic for hereditary transthyretin amyloidosis related cardiomyopathy by multiple submitters. The c.424G>A variant is observed almost exclusively in individuals of African American ancestry (~1.5% minor allele frequency) in population databases (gnomAD v2.1.1 and v3.1.2), suggesting it being a founder mutation for this population. The c.424G>A variant is located in the exon 4 of this 4-exon gene and replaces an evolutionarily conserved valine amino acid with isoleucine at position 142 of the encoded protein (p.Val142Ile) (also known as p.Val122Ile based on nomenclature for the circulating protein after N-terminal peptide cleavage) [PMIDs: 2646319, 2349941]. Functional studies demonstrated that the p.(Val142Ile) variant confer amyloidogenic properties via causing conformational changes and reducing the stability of the physiologic TTR tetramer [PMIDs: 17503405, 18276611]. Based on available evidence this c.424G>A p.Val142Ile variant identified in TTR is classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000078674	SCV001449972	pathogenic	not provided	2019-11-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000014368	SCV001524701	pathogenic	Familial amyloid neuropathy	2022-11-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000078674	SCV001715218	pathogenic	not provided	2021-02-23	criteria provided, single submitter	clinical testing	PS3, PS4
DASA	RCV000014368	SCV002061278	pathogenic	Familial amyloid neuropathy	2022-01-05	criteria provided, single submitter	clinical testing	The c.424G>A;p.(Val142Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13426; OMIM: 176300.0009; PMID: 12874414; PMID: 25551524; PMID: 30938420; PMID: 31359320; PMID: 27720586; PMID: 26123279; PMID:11752443) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 12874414, 27758856, 27720586, 11752443) - PS3. The variant is located in a mutational hot spot and/or critical and well-established functional domain (TR_THY domain) - PM1. and allele frequency is greater than expected for disorder -BS1. In summary, the currently available evidence indicates that the variant is pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000078674	SCV002502738	pathogenic	not provided	2022-03-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000078674	SCV002563460	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	TTR: PP1:Strong, PS3, PS4
Variantyx, Inc.	RCV000014368	SCV002754521	pathogenic	Familial amyloid neuropathy	2022-11-07	criteria provided, single submitter	clinical testing	This is a nonsynonymous variant in the TTR gene (OMIM 176300). Heterozygous pathogenic variants in this gene are associated with autosomal dominant hereditary transthyretin-related amyloidosis. This is an established founder variant in the African population, with an allele frequency of >3% in African Americans (PMID: 9017939, 26123279). It has been observed in individuals with transthyretin-related amyloidosis in both the homozygous and the heterozygous state (PMID: 25846356, 24184229, 12050338, 19781421, 22745357) (PS4). Functional studies have shown that this variant alters TTR protein function (PMID: 11752443, 12874414, 15820680, 17503405, 22184092, 24474780) (PS3). Multiple computational algorithms predict a deleterious effect for this substitution (PP3). This variant has a 1.654% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on current evidence, this variant is classified as pathogenic for autosomal dominant hereditary transthyretin-related amyloidosis.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000014368	SCV003806882	pathogenic	Familial amyloid neuropathy	2022-09-16	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 strong, PS4 strong, PP1 strong
3billion	RCV000014368	SCV003841759	pathogenic	Familial amyloid neuropathy	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 11752443). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013426). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11752443, 2349941, 25551524, 25819286, 26537620). Different missense changes at the same codon (p.Val142Ala, p.Val142Leu) have been reported to be associated with TTR related disorder (ClinVar ID: VCV001333466 / PMID: 10211412, 24101130 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335038	SCV004046214	pathogenic	TTR-related disorders		criteria provided, single submitter	clinical testing	This variant is also known as p.Val122Ile by legacy nomenclature. The c.424G>A (p.Val142Ile) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.15% (435/282792) and in the homozygous state in three individuals. It is found in approximately 3.5% of African Americans (PMID: 26123279). This variant has been identified as a causative allele for late-onset cardiac amyloidosis; specifically, it is a common cause of amyloidosis in individuals of African American ancestry with affected individuals typically presenting after the sixth decade of life (PMID: 20435197, 22877808, 24070600, 24184229). This variant has also been observed in individuals from other ancestries with a similar amyloidosis phenotype (PMID: 25846356, 22745357). Experimental studies have shown that this variant weakens the stability of TTR tetramer protein complexes in plasma and cerebrospinal fluid (PMID: 15820680, 17503405, 18276611). Based on the available evidence, c.424G>A (p.Val142Ile) is classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000014368	SCV004046301	pathogenic	Familial amyloid neuropathy		criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in patients with Transthyretin-related Amyloid Cardiomyopathy (PMID: 12050338, 19781421, 22745357, 24184229, 25846356). The c.424G>A (p.Val142Ile) variant is present in the gnomAD population database at a frequency of 0.15% (417/277140) in the heterozygous state and a frequency of 0.001% (3/282792) in the homozygous state. The c.424G>A (p.Val142Ile) variant is found in approximately 3.5% of individuals with African American ancestry (PMID: 26123279, 34461737). This variant results in the cardiac amyloidosis phenotype (see Gene Information section for details on this specific phenotype) (PMID: 24070600, 24184229, 20435197, 22877808, 34461737). This variant has also been observed in individuals from other ancestries with a similar phenotype (PMID: 25846356, 22745357). Experimental studies have shown this variant weakens the stability of the TTR tetramer protein complexes (PMID: 15820680, 17503405, 18276611). The c.424G>A (p.Val142Ile) variant affects a weakly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.424G>A, p.Val142Ile variant is classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415699	SCV004116698	pathogenic	TTR-related condition	2024-03-01	criteria provided, single submitter	clinical testing	The TTR c.424G>A variant is predicted to result in the amino acid substitution p.Val142Ile. This variant, also referred to as p.Val122Ile using legacy nomenclature, has been reported to be causative for autosomal dominant hereditary amyloidosis and typically presents as familial amyloid cardiomyopathy (Ando et al. 2013. PubMed ID: 23425518; Penchala et al. 2013. PubMed ID: 23716704; Jacobson et al. 1990. PubMed ID: 2349941; Buxbaum et al. 2010. PubMed ID: 20435197; Dungu et al. 2016. PubMed ID: 27618855; Lopes et al. 2019. PubMed ID: 31554435). It has also been reported as pathogenic by multiple, independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/13426/). This variant is reported in 1.6% of alleles in individuals of African descent in gnomAD, which is consistent with variant being a founder event with high frequency in individuals of African descent (Jacobson et al. 1997. PubMed ID: 9017939; Jacobson et al. 2015. PubMed ID: 26123279). This variant is interpreted as pathogenic.
OMIM	RCV000014368	SCV000034617	pathogenic	Familial amyloid neuropathy	2003-07-22	no assertion criteria provided	literature only
Gharavi Laboratory, Columbia University	RCV000078674	SCV000809425	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Reproductive Health Research and Development, BGI Genomics	RCV000014368	SCV001142480	pathogenic	Familial amyloid neuropathy	2020-01-06	no assertion criteria provided	curation	NM_000371.3:c.424G>A (p.Val142Ile) was reported as Val122Ile in the TTR gene, and it has an allele frequency of 0.016 in African subpopulation in the gnomAD database. Functional studies demonstrate that Val122Ile affect TTR protein function (PMID: 18276611). V122I variant is the most common amyloidogenic mutation worldwide, associated with familial amyloidotic cardiomyopathy in individuals of African descent. It is estimated that 4% of African Americans are heterozygous for the V122I variant, with an age of onset at around 60 years of age (PMID: 18276611). Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PS4; PP4; PP3
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000078674	SCV001742338	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000014368	SCV001749428	not provided	Familial amyloid neuropathy		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 06-01-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Clinical Genetics, Academic Medical Center	RCV000078674	SCV001920578	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000078674	SCV001931404	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078674	SCV001957782	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000078674	SCV001975196	pathogenic	not provided		no assertion criteria provided	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000014368	SCV002029170	pathogenic	Familial amyloid neuropathy	2021-10-18	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000078674	SCV002035782	pathogenic	not provided		no assertion criteria provided	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV003319166	SCV004022490	likely pathogenic	Tip-toe gait	2022-12-19	no assertion criteria provided	clinical testing