Submissions for variant NM_000371.4(TTR):c.148G>A (p.Val50Met)

gnomAD frequency: 0.00004  dbSNP: rs28933979

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000014359	SCV000053242	pathogenic	Familial amyloid neuropathy	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000014359	SCV000203972	pathogenic	Familial amyloid neuropathy	2021-04-06	criteria provided, single submitter	clinical testing	The p.Val50Met variant in TTR (also described as p.Val30Met in the literature) is a common variant in individuals with hereditary transthyretin amyloidosis (ATTR), especially in those of Portuguese, Swedish and Japanese ancestry. It has been reported in a multitude of affected individuals and segregated with disease in >100 affected individuals from >95 families, although >100 individuals who carry this variant were found to be asymptomatic, suggesting reduced penetrance (Coelho 1994 PMID: 8071954, Hattori 2003 PMID: 14986482, Hellman 2008 PMID: 18925456, Rapezzi 2012 PMID: 22745357, Bekircan-Kurt 2015 PMID: 26115788, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 13417) and has been identified in 0.017% (19/113746) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although this frequency is high in the general population, it is consistent with reduced penetrance. Two mouse models showed amyloid deposition and an inflammatory response similar to human familial transthyretin amyloidosis, and in vitro functional studies provide some evidence that this variant impacts protein function by reducing conformational stability (Yi 1991 PMID: 1992765, Altland 2007 PMID: 17503405, Goncalves 2014 PMID: 24800914). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant transthyretin amyloidosis, with reduced penetrance. ACMG/AMP criteria applied: PS4, PP1_Strong, PS3.
GeneDx	RCV000159423	SCV000209369	pathogenic	not provided	2023-03-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Also known as V30M; This variant is associated with the following publications: (PMID: 24455802, 24164154, 15820680, 18276611, 19602727, 32674397, 26521788, 28475415, 29540472, 26513367, 28635949, 34059423, 34440326, 34461735, 30811423, 18925456, 26537620, 26600212, 24555660, 23387326, 23993291, 22531659, 23080516, 17503405, 24800914, 24474780, 26115039, 27589730, 26104852, 27793437, 6736244, 18606975, 26096568, 19808383, 22382560, 26017327, 22620962, 24601850, 23833285, 22745357, 25525159, 25550818, 26115788, 19364362, 24046394, 20209591, 24101130, 22592564, 30243104, 30019395, 30213731, 31343348, 31371117, 30572722, 31718691, 29520877, 31919945, 32852783, 34024775, 3479441, 24395461, 3229002, 31589614, 32269295, 33373035, 11523162, 32893242, 3762958, 18506713, 32528171, 26587769, 32880476, 32399692, 32376792, 33726816, 35751086, 31701603, 35903975, 35945697, 35358243, 34980537, 35893595, 33739616, 34658264, 20301373)
Invitae	RCV000014359	SCV000541951	pathogenic	Familial amyloid neuropathy	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces valine with methionine at codon 50 of the TTR protein (p.Val50Met). There is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs28933979, gnomAD 0.02%). This missense change has been observed in individual(s) with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) (PMID: 22620962, 22745357, 23833285, 24455802, 24555660, 26115788). It is commonly reported in individuals of Portuguese, Swedish and Japanese ancestry (PMID: 22620962, 23833285, 24555660). This variant is also known as p.Val30Met. ClinVar contains an entry for this variant (Variation ID: 13417). 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, 23080516, 24601850, 25550818). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc	RCV000159423	SCV000616207	pathogenic	not provided	2023-07-13	criteria provided, single submitter	clinical testing	Val50Met is the most common variant associated with TTR-related hereditary amyloidosis; 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 has also been reported in patients with cardiac involvement with and without neuropathy (PMID: 19808383, 20209591, 23993291). This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. This variant is also referred to as Val30Met in published literature. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies showed this variant caused reduced stability of the protein (PMID: 17503405, 15820680).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000159423	SCV000884814	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	The TTR c.148G>A; p.Val50Met variant (rs28933979), also known as Val30Met, is the most common pathogenic TTR variant associated with familial amyloidotic polyneuropathy worldwide (Parman 2016). The variant has a variable clinical presentation ranging from asymptomatic carriers to systemic disease, having early-late onset disease subtypes (Arvidsson 2015, Beirao 2015, Coelho 2017, Parman 2016). Functional studies suggest the variant refolds from monomers to tetramers at a slower rate compared to wildtype (Jesus 2016), has decreased stability in the folded state (Altland 2007), and impairs the inflammatory response necessary for nerve regeneration (Goncalves 2014). This variant is reported as pathogenic in ClinVar (Variation ID: 13417), and observed in the general population with an overall allele frequency of 0.01% (25/246236 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.711). Additionally, other variants at this codon (p.Val50Ala, p.Val50Leu) have been reported in individuals with amyloid neuropathy and are considered pathogenic (Altland 2007, Suhr 2009). Based on available information, the p.Val50Met 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. Arvidsson S et al. Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition. PLoS One. 2015 Nov 23;10(11):e0143456. PMID: 26600306. Beirao JM et al. Ophthalmological manifestations in hereditary transthyretin (ATTR V30M) carriers: a review of 513 cases. Amyloid. 2015;22(2):117-22. PMID: 26096568. Coelho T et al. Clinical measures in transthyretin familial amyloid polyneuropathy. Muscle Nerve. 2017 Mar;55(3):323-332. PMID: 27422379. Goncalves NP et al. The inflammatory response to sciatic nerve injury in a familial amyloidotic polyneuropathy mouse model. Exp Neurol. 2014 Jul;257:76-87. PMID: 24800914. Jesus CS et al. A New Folding Kinetic Mechanism for Human Transthyretin and the Influence of the Amyloidogenic V30M Mutation. Int J Mol Sci. 2016 Aug 31;17(9). PMID: 27589730. Parman Y et al. Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP. Curr Opin Neurol. 2016 Feb;29 Suppl 1:S3-S13. PMID: 26734951. Suhr OB et al. Report of five rare or previously unknown amyloidogenic transthyretin mutations disclosed in Sweden. Amyloid. 2009 Dec;16(4):208-14. PMID: 19922332.
Fulgent Genetics, Fulgent Genetics	RCV002476964	SCV000893493	pathogenic	Hyperthyroxinemia, dystransthyretinemic; Familial amyloid neuropathy; Carpal tunnel syndrome 1	2021-12-26	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770555	SCV000902003	pathogenic	Cardiomyopathy	2023-01-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000159423	SCV001245840	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	TTR: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PS3:Supporting
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173292	SCV001336376	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000014359	SCV001423810	pathogenic	Familial amyloid neuropathy	2019-10-21	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the TTR c.148G>A (p.Val50Met) missense variant has been identified as the most common variant in individuals with familial transthyretin amyloidosis (ATTR), with an estimated frequency of 0.04 in affected individulas from Sweden. This variant, also referred to as p.Val30Met in the literature, has been reported in both a homozygous and a heterozygous state (Andres et al. 2018; Hellman et al. 2008; Sekijima 2018). The age of onset of disease for individuals carrying the variant differs between populations, with Portugese and Japanese carriers presenting with earlier onset at 33 years. Overall, the penetrance increased with age and was significantly higher when the variant was inherited from the mother than from the father (Hellman et al. 2008). The p.Val50Met variant is reported at a frequency of 0.000487 in the Other population of the Genome Aggregation Database. This allele frequency is high but may be consistent with reduced penetrance. Transgenic mice carrying the p.Val50Met variant show higher amyloid deposition in the gastrointestinal tract, renal glomeruli, myocardium, small vascular walls, and thyroid with advancing age, which is consistent with findings from patient autopsy reports (Yi et al. 1991). Goncalves et al. (2014) showed a higher TTR expression, tissue specific deposition in nerves, reduced inflammatory response, and impaired regenerative process in injured nerves of transgenic p.Val50Met mice compared to their wild type counterparts. Based on the collective evidence and application of the ACMG criteria, the p.Val50Met variant is classified as pathogenic for familial transthyretin amyloidosis.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000159423	SCV001447620	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000159423	SCV001449640	pathogenic	not provided	2016-04-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000159423	SCV002022478	pathogenic	not provided	2021-11-04	criteria provided, single submitter	clinical testing
DASA	RCV000014359	SCV002061162	pathogenic	Familial amyloid neuropathy	2022-01-05	criteria provided, single submitter	clinical testing	The c.148G>A;p.(Val50Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 13417; PMID: 25550818; 15820680; 24601850; 22745357; 17503405; 30328212; 26088020; 20301373; OMIM: 176300.0001) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 25519307, 26088020) - .PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Transthyretin domain) - PM1. The variant is present at low allele frequencies population databases (rs28933979– gnomAD 0.0004600%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (Clinvar ID: 13430; 13440; 13465) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 26115788) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000159423	SCV002502303	pathogenic	not provided	2022-02-16	criteria provided, single submitter	clinical testing
3billion	RCV000014359	SCV002521706	pathogenic	Familial amyloid neuropathy	2024-03-11	criteria provided, single submitter	clinical testing	The variant is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org) dataset (total allele frequency: 0.010%). 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:25519307, 26088020). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.71; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013417). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID:26115788). Different missense changes at the same codon (p.Val50Ala, p.Val50Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013430, VCV000013440). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Johns Hopkins Genomics, Johns Hopkins University	RCV000014359	SCV002570305	pathogenic	Familial amyloid neuropathy	2022-02-12	criteria provided, single submitter	clinical testing	This TTR variant (rs28933979) is rare (<0.1%) in a large population dataset (gnomAD: 26/251462 total alleles; 0.01%; no homozygotes) and has been reported in ClinVar. This variant, c.148G>A (p.Val50Met), also described as p.Val30Met in the literature, is the most common pathogenic variant in individuals with familial transthyretin amyloidosis. Individuals with this variant have a variable clinical presentation ranging from asymptomatic carriers to systemic disease, consistent with reduced penetrance. Other pathogenic variants at this same nucleotide position have been associated with amyloidosis, including c.148G>C (p.Val50Leu). Experimental studies demonstrate that this missense variant significantly affects protein stability. In addition, transgenic mice containing this variant showed amyloid deposition and an inflammatory response similar to human familial transthyretin amyloidosis. This variant was also reported in the patient's symptomatic father, who was tested by an outside laboratory. We consider this variant to be pathogenic.
MGZ Medical Genetics Center	RCV000014359	SCV002581491	pathogenic	Familial amyloid neuropathy	2022-02-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390106	SCV002698968	pathogenic	Cardiovascular phenotype	2021-08-19	criteria provided, single submitter	clinical testing	The p.V50M pathogenic mutation (also known as c.148G>A and V30M), located in coding exon 2 of the TTR gene, results from a G to A substitution at nucleotide position 148. The valine at codon 50 is replaced by methionine, an amino acid with highly similar properties. This mutation was first reported in TTR-related amyloid protein of tissue samples from Portuguese individuals with familial amyloidotic polyneuropathy (Saraiva MJ et al. J. Clin. Invest., 1984 Jul;74:104-19). This mutation has been detected in numerous individuals with hereditary transthyretin amyloidosis and is reported to be the most common TTR mutation; it is associated with the polyneuropathy type of familial TTR amyloidosis, but age of onset and severity are considered variable (Soares ML et al. Eur. J. Hum. Genet., 2004 Mar;12:225-377; Du K et al. Ann Clin Transl Neurol, 2021 04;8:831-841; Andr&eacute;s N et al. Neurologia (Engl Ed) Oct;33:583-589 ). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV003914842	SCV004745647	pathogenic	TTR-related condition	2024-03-01	criteria provided, single submitter	clinical testing	The TTR c.148G>A variant is predicted to result in the amino acid substitution p.Val50Met. This variant, also reported as p.Val30Met using legacy nomenclature, has been reported as one of the most common causative variants for hereditary transthyretin amyloidosis with individuals typically presenting with familial amyloidotic polyneuropathy/TTR-FAP (Ando et al. 2013. PubMed ID: 23425518; Saraiva et al. 1984. PubMed ID: 6736244; Holmgren et al. 1994. PubMed ID: 8064809; Skrahina et al. 2021. PubMed ID: 34658264). Penetrance for this variant is incomplete and increases with age (Hellman et al. 2008. PubMed ID: 18925456). Functional studies found this variant disrupts protein function (Altland et al. 2007. PubMed ID: 17503405; Jesus et al. 2016. PubMed ID: 27589730). This variant is reported in 0.017% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant has also been consistently interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/13417/). Additionally, alternate missense variants affecting the same amino acid (p.Val50Leu, p.Val50Ala, p.Val50Gly) have been reported in individuals with hereditary transthyretin amyloidosis (Murakami et al. 1992. PubMed ID: 1520326; Altland et al. 2007. PubMed ID: 17503405; Zeldenrust et al. 2012. PubMed ID: 22620962). This variant is interpreted as pathogenic.
OMIM	RCV000014359	SCV000034608	pathogenic	Familial amyloid neuropathy	2008-07-01	no assertion criteria provided	literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000159423	SCV000280559	pathogenic	not provided	2012-11-20	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Val30Met (aka p.Val50Met) in TTR. This variant has been seen in dozens of families with transthyretin-related amyloidosis. It is one of the most common disease-causing variants in TTR. This variant has been reported in association with autonomic neuropathy, ocular problems, leptomeningeal features, and polyneuropathy. Cardiomyopathy and nephropathy can be late stage manifestations. It has been observed in Portugal, Sweden, Japan, and the US. Age of onset is variable with this variant ranging from 17 to 80 years old. In endemic areas of Japan average onset is 40yo while in other areas of Japan it is 63 years. Individuals of Portugese ancestry have an average onset of 34 years. Individuals of Swedish, French, or British ancestry with this variant have a much later onset. Three other variants at this same codon have been associated with amyloidosis including p.Val30Ala, p.Val30Gly, p.Val30Leu. There is no variation at codon 30 list in the NHLBI exome sequencing project, which currently includes data on ~6500 Caucasian and African American individuals (as of November 16th, 2012).
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000014359	SCV001739334	pathogenic	Familial amyloid neuropathy	2021-03-30	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000159423	SCV001741725	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000014359	SCV001749981	not provided	Familial amyloid neuropathy		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 05-09-2019 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	RCV000159423	SCV001917062	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000159423	SCV001929969	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000159423	SCV001952986	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000159423	SCV001975327	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000159423	SCV002035438	likely pathogenic	not provided		no assertion criteria provided	clinical testing