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

gnomAD frequency: 0.00013  dbSNP: rs200112094

Total submissions: 8

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	2023-05-03	criteria provided, single submitter	clinical testing	Observed in an individual with DCM in the published literature; however, detailed clinical information was not provided (Mazzarotto et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23861362, 31983221)
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	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 419 of the LAMA4 protein (p.Met419Thr). This variant is present in population databases (rs200112094, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with LAMA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 192120). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Ambry Genetics	RCV002415738	SCV002677643	uncertain significance	Cardiovascular phenotype	2023-07-24	criteria provided, single submitter	clinical testing	The p.M419T variant (also known as c.1256T>C), located in coding exon 10 of the LAMA4 gene, results from a T to C substitution at nucleotide position 1256. The methionine at codon 419 is replaced by threonine, an amino acid with similar properties. This variant has been detected in one individual from a dilated cardiomyopathy cohort, as well as in one sudden infant death case; however, limited clinical details were provided for both (Campuzano O et al. Forensic Sci Int Genet, 2018 11;37:54-63; Mazzarotto F et al. Circulation, 2020 02;141:387-398). This alteration has also been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000172552	SCV000925111	uncertain significance	not provided	2017-02-24	no assertion criteria provided	provider interpretation
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172552	SCV001956984	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172552	SCV001976167	uncertain significance	not provided		no assertion criteria provided	clinical testing