ClinVar Miner

Submissions for variant NM_000371.4(TTR):c.148G>A (p.Val50Met) (rs28933979)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000014359 SCV000053242 pathogenic Amyloidogenic transthyretin amyloidosis 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
GeneDx RCV000159423 SCV000209369 pathogenic not provided 2018-03-01 criteria provided, single submitter clinical testing The V50M pathogenic variant in the TTR gene (also reported as V30M using alternate nomenclature) is a common variant associated with familial TTR amyloidosis (Sekijima Y et al., 2012). Individuals with this pathogenic variant typically present with peripheral and autonomic neuropathy, as well as leptomeningeal amyloidosis. Vitreous opacification, cardiomyopathy, and nephropathy may develop later in life. The V50M variant is observed in 17/66740 (0.03%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Furthermore, missense variants in this residue (V50L/A/G) and in nearby residues (A45S/T, V48M, V52G/A) have been reported in the Human Gene Mutation Database in association with TTR amyloidosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. The T50M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, this substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. Nevertheless, functional studies conducted by Altland et al. (2007) demonstrated that plasma samples containing V50M (referred to as V30M) had a significantly higher percentage of TTR monomers in the unfolded state compared to wild-type. Furthermore, mice harboring this variant (also referred to as V30M) showed a decreased inflammatory immune response after injury compared to wild type mice (Goncalves et al., 2014). Therefore, the presence of this pathogenic variant indicates that this individual is at increased risk to develop late-onset TTR amyloidosis. However, other genetic and environmental factors may influence disease expression and severity, and some pathogenic variant carriers may never become symptomatic.
Invitae RCV000014359 SCV000541951 pathogenic Amyloidogenic transthyretin amyloidosis 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 50 of the TTR protein (p.Val50Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs28933979, ExAC 0.03%). This variant is one of the most commonly known causes of hereditary amyloidosis in individuals with Portuguese, Swedish and Japanese ancestry (PMID: 22620962, 23833285, 24555660), although it has also been reported in affected individuals of other ancestries (PMID: 26115788, 24455802, 22745357). This variant is also known as p.Val30Met in the literature. ClinVar contains an entry for this variant (Variation ID: 13417). In an experimental study using a cell model, this variant was shown to affect protein stability (PMID: 15820680). Furthermore, observations from studies in affected individuals have shown that this variant affects protein expression and solubility (PMID: 25550818, 24601850, 23080516). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000159423 SCV000616207 pathogenic not provided 2019-10-30 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. This variant is also referred to as Val30Met in published literature. This variant has also been reported in patients with cardiac involvement with and without neuropathy. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000035 SCV000884814 pathogenic none provided 2020-02-10 criteria provided, single submitter clinical testing The TTR c.148G>A; p.Val50Met variant (rs28933979), also known as p.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. The valine at codon 50 is a highly conserved residue located in the thyroxine binding site, and the p.Val50Met variant is computationally predicted to be damaging to the protein (SIFT, PolyPhen2). 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. 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. Beirao JM et al. Ophthalmological manifestations in hereditary transthyretin (ATTR V30M) carriers: a review of 513 cases. Amyloid. 2015;22(2):117-22. Coelho T et al. Clinical measures in transthyretin familial amyloid polyneuropathy. Muscle Nerve. 2017 Mar;55(3):323-332. 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. 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). 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. Suhr OB et al. Report of five rare or previously unknown amyloidogenic transthyretin mutations disclosed in Sweden. Amyloid. 2009 Dec;16(4):208-14.
Fulgent Genetics,Fulgent Genetics RCV000763026 SCV000893493 pathogenic Carpal tunnel syndrome; Dystransthyretinemic euthyroidal hyperthyroxinemia; Amyloidogenic transthyretin amyloidosis 2018-10-31 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770555 SCV000902003 pathogenic Cardiomyopathy 2016-03-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000159423 SCV001245840 pathogenic not provided 2019-11-01 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre RCV001173292 SCV001336376 pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000014359 SCV001423810 pathogenic Amyloidogenic transthyretin amyloidosis 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 Karolinska University Hospital,Karolinska University Hospital RCV000159423 SCV001449640 pathogenic not provided 2016-04-08 criteria provided, single submitter clinical testing
OMIM RCV000014359 SCV000034608 pathogenic Amyloidogenic transthyretin amyloidosis 2008-07-01 no assertion criteria provided literature only
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000014359 SCV000203972 pathogenic Amyloidogenic transthyretin amyloidosis 2006-11-13 no assertion criteria provided clinical testing
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).

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