ClinVar Miner

Submissions for variant NM_001105206.3(LAMA4):c.1277T>C (p.Met426Thr) (rs200112094)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172552 SCV000050964 likely benign not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000172552 SCV000572975 uncertain significance not provided 2018-02-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the LAMA4 gene. The M419T variant has been previously reported in two individuals from a cohort of patients undergoing exome sequencing who were not selected for a history of cardiac arrhythmia or cardiomyopathy, or family history of sudden cardiac death (Ng et al., 2013). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M419T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across most species with threonine being the wild type in the hedgehog. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000624643 SCV000740586 uncertain significance Primary familial hypertrophic cardiomyopathy 2016-05-31 criteria provided, single submitter clinical testing
Invitae RCV000707706 SCV000836815 uncertain significance Dilated cardiomyopathy 1JJ 2019-11-22 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 419 of the LAMA4 protein (p.Met419Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs200112094, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with LAMA4-related disease. ClinVar contains an entry for this variant (Variation ID: 192120). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000172552 SCV000925111 uncertain significance not provided 2017-02-24 no assertion criteria provided provider interpretation

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