ClinVar Miner

Submissions for variant NM_000371.4(TTR):c.424G>A (p.Val142Ile) (rs76992529)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000030575 SCV000053250 pathogenic Amyloid Cardiomyopathy, Transthyretin-related 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
GeneDx RCV000078674 SCV000209380 pathogenic not provided 2018-11-28 criteria provided, single submitter clinical testing The V142I variant in the TTR gene, also reported as V122I due to the use of alternative nomenclature, is a common amyloidogenic TTR pathogenic variant in the African-American population, seen in approximately 3-4% of individuals (Jacobson et al., 1990; Jacobson et al., 1997a; Jacobson et al., 1997b; Yamashita et al., 2005). Allele frequency data from a more recent study by Jacobson et al. (2016) was consistent with V142I originating in a small number of founder carriers in southern West Africa. Additionally, the V142I variant has been reported in individuals of varying ethnic backgrounds in the Online Registry for Mutations in Hereditary Amyloidosis. V142I has been reported in patients with familial amyloid cardiomyopathy and senile systemic amyloidosis (SSA) who were heterozygous or homozygous for V142I (Jacobson et al., 1990; Jacobson et al., 1997a; Jacobson et al., 1997b). 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). Peripheral and autonomic neuropathy are absent or less evident in individuals with this pathogenic variant (Sekijima et al., 2012).Functional studies by Jiang et al. (2001) demonstrated V142I renders the TTR complex unstable, leading to unfolding and lower tetramer stability. Askanas et al. (2003) demonstrated that cultured skeletal muscle fibers from patients harboring the V142I variant had vacuolar degeneration, congophilic inclusions, clusters of immunocolocalizing beta-amyloid and TTR accumulations. Another variant affecting the same residue (V142A) has been reported in association with cardiac amyloidosis and peripheral neuropathy (Connors et al., 2003; Stenson et al., 2014). In addition, V142I has been observed in multiple other unrelated individuals who have been referred for genetic testing of cardiomyopathy at GeneDx.
Invitae RCV000014368 SCV000284750 pathogenic Amyloidogenic transthyretin amyloidosis 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 142 of the TTR protein (p.Val142Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs76992529, ExAC 1.5%). This variant has been observed in individuals with transthyretin amyloidosis (PMID: 25846356, 24184229, 12050338, 19781421, 22745357). This variant is a common cause of amyloidosis in individuals of African American ancestry and is present in 3.5% of this population (PMID: 20435197, 22877808). It has also been observed in individuals of other ethnic backgrounds (PMID: 25846356, 22745357). This variant is also known as p.Val122Ile in the literature. ClinVar contains an entry for this variant (Variation ID: 13426). This variant has been reported to affect TTR protein function (PMID: 17503405, 18276611, 15820680). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000243161 SCV000318173 pathogenic Cardiovascular phenotype 2019-08-22 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Other strong data supporting pathogenic classification
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078674 SCV000331406 pathogenic not provided 2013-05-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000014368 SCV000408397 pathogenic Amyloidogenic transthyretin amyloidosis 2016-06-14 criteria provided, single submitter clinical testing The c.424G>A (p.Val142Ile) variant, also known as p.Val122Ile, has been described as the most common pathogenic variant in familial transthyretin amyloidosis patients and is known to present in a heterozygous state at a frequency of 3.5% in the African American population (Sekijima et al. 2012; Jacobsen et al. 2015). The variant is associated with an exclusively cardiac phenotype, a severe restrictive cardiomyopathy with absence of significant neurological involvement. Prior to age 60 the variant does not appear to affect mortality or cardiac function. However, after age 60, the carriers of the variant demonstrated earlier onset of disease with an increased risk for mortality and congestive heart failure (Buxbaum et al. 2010; Reddi et al. 2014; Quarta et al. 2015; Damy et al. 2016). Across a selection of the available literature, the p.Val142Ile variant has been identified in a homozygous state in 19 patients, in a compound heterozygous state in two patients, and in a heterozygous state in 36 patients (Jacobsen et al. 1990; Jacobson et al. 1997; Buxbaum et al. 2010; Givens et al. 2013; Reddi et al. 2014; Dubrey et al. 2014; Carr et al. 2015; Quarta et al. 2015; Damy et al. 2016; Cappelli et al. 2016). The p.Val142Ile variant was absent from 43 control alleles but is reported at a frequency of 0.02778 in the Yoruba in Ibadan, Nigeria, population of the 1000 Genomes Project. This allele frequency is high but is consistent with the disease prevalence. 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 (Jiang et al. 2001; Steward et al. 2008). Based on the collective evidence, the p.Val142Ile variant is classified as pathogenic for familial transthyretin amyloidosis.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000999849 SCV000605508 pathogenic not specified 2018-08-06 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, see ClinVar link and references therein). 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 main 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 population with an overall allele frequency of 1.6% (385/24034 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 (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to ClinVar database for p.Val142Ile: https://www.ncbi.nlm.nih.gov/clinvar/variation/13426/ Altland K et al. Genetic microheterogeneity of human transthyretin detected by IEF. Electrophoresis. 2007 Jun;28(12):2053-64. Askanas V et al. Transthyretin Val122Ile, accumulated Abeta, and inclusion-body myositis aspects in cultured muscle. Neurology. 2003 Jul 22;61(2):257-60. 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. 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 Jan 19. 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. 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. 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. 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. Sekijima Y et al. The biological and chemical basis for tissue-selective amyloid disease. Cell. 2005 Apr 8;121(1):73-85. 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. 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. Quarta CC et al. The amyloidogenic V122I transthyretin variant in elderly black Americans. N Engl J Med. 2015 Jan 1;372(1):21-9.
Fulgent Genetics,Fulgent Genetics RCV000515257 SCV000611333 pathogenic Carpal tunnel syndrome; Dystransthyretinemic euthyroidal hyperthyroxinemia; Amyloidogenic transthyretin amyloidosis 2017-05-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000078674 SCV000616219 pathogenic not provided 2015-08-19 criteria provided, single submitter clinical testing
Gharavi Laboratory,Columbia University RCV000078674 SCV000809425 pathogenic not provided 2018-09-16 criteria provided, single submitter research
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735409 SCV000854564 pathogenic Anemia; Pancytopenia; Pneumonia; Bone marrow hypocellularity criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000211747 SCV000902011 pathogenic Cardiomyopathy 2017-09-07 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000014368 SCV000995173 pathogenic Amyloidogenic transthyretin amyloidosis 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 Amyloidogenic transthyretin amyloidosis 2019-05-28 criteria provided, single submitter clinical testing
OMIM RCV000014368 SCV000034617 pathogenic Amyloidogenic transthyretin amyloidosis 2003-07-22 no assertion criteria provided literature only
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000014368 SCV000060031 not provided Amyloidogenic transthyretin amyloidosis 2018-09-14 no assertion provided clinical testing
Reproductive Health Research and Development,BGI Genomics RCV000014368 SCV001142480 pathogenic Amyloidogenic transthyretin amyloidosis 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

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