ClinVar Miner

Submissions for variant NM_007375.4(TARDBP):c.1009A>G (p.Met337Val)

gnomAD frequency: 0.00001  dbSNP: rs80356730
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Neurology-Cell Therapy Center, Hanyang University RCV000005539 SCV004023203 pathogenic Amyotrophic lateral sclerosis type 10 2023-03-15 criteria provided, single submitter clinical testing The Met337Val variant in TARDBP has been reported in Western countries and Asia with autosomal dominant amyotrophic lateral sclerosis, segregated with the disease in over 10 affected relatives (Sreedharan 2008, Kirby 2010, Tamaoka 2010, Xu 2018), and was absent from large population studies. Additionally, studies indicate that the Met337Var variant transgenic mouse presented worsened dose-dependent disease phenotype in terms of motor dysfunction, neurodegeneration, gliosis, and development of ubiquitin and phosphorylated TDP-43 pathology (Janssens 2013). In summary, the Met337Val variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and functional evidence.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001090806 SCV001446728 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001090806 SCV001246537 pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000693006 SCV000820859 pathogenic Amyotrophic lateral sclerosis type 10; FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, TARDBP-RELATED 2024-11-05 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 337 of the TARDBP protein (p.Met337Val). This variant is present in population databases (rs80356730, gnomAD 0.002%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (ALS) (PMID: 18309045, 20154440, 28430856, 28709720). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5228). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TARDBP protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects TARDBP function (PMID: 18309045, 19465477, 20600671, 23401527, 23827948, 24143176, 24507191). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000005539 SCV000041191 not provided Amyotrophic lateral sclerosis type 10 no assertion provided literature only Convincing evidence of segregation.
OMIM RCV000005539 SCV000025721 pathogenic Amyotrophic lateral sclerosis type 10 2008-03-21 no assertion criteria provided literature only

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