Submissions for variant NM_001105206.3(LAMA4):c.1475T>A (p.Leu492His)

gnomAD frequency: 0.00093  dbSNP: rs3752579

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171982	SCV000050963	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037335	SCV000060992	benign	not specified	2015-10-22	criteria provided, single submitter	clinical testing	p.Leu485His in exon 12 of LAMA4: This variant is not expected to have clinical s ignificance because it has been identified in 1.6% (189/11562) of Latino chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3752579).
GeneDx	RCV000037335	SCV000250523	benign	not specified	2015-04-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082708	SCV000556713	benign	Dilated cardiomyopathy 1JJ	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620922	SCV000735785	benign	Cardiovascular phenotype	2016-05-14	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000853005	SCV000995760	benign	Cardiomyopathy; Hypertrophic cardiomyopathy	2018-12-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001082708	SCV002047939	benign	Dilated cardiomyopathy 1JJ	2023-11-11	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000037335	SCV000280170	uncertain significance	not specified	2015-07-24	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. LAMA4 p.Leu485His We classify this as a VUS-probably benign. This variant has not been published in the literature in association with cardiomyopathy. By contrast, it has been detected in presumably unaffected individuals in population datasets (see below). Furthermore, the LAMA4 gene might rightly be called a “gene of uncertain significance” given the paucity of data: there are only 2 variants listed in HGMD for this gene, both associated with DCM. No variation at residues near Leu485His has been associated with cardiomyopathy (HGMD professional version as of January 17, 2014). This is a non-conservative amino acid change, resulting in the replacement of a nonpolar Leucine with a positively-charged Histidine. This location is conserved across species. In silico analysis was inconsistent with regard to the effect on protein structure/function. In total the variant has been seen in 10 individuals from publicly available population datasets. It was observed in 10 individuals in the 1000 Genomes Project: 6 Han Chinese, 2 Japanese, and 2 Mexican (http://browser.1000genomes.org/index.htm) as of April 15, 2014. This raises the possibility that it may be a benign variant found more often in certain ethnicities. This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. It is listed in dpSNP as rs3752579, with multiple submitters including 1000 Genomes.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000037335	SCV001741678	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000037335	SCV001925530	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000037335	SCV001954032	benign	not specified		no assertion criteria provided	clinical testing