Submissions for variant NM_001105206.3(LAMA4):c.3175G>A (p.Val1059Met)

gnomAD frequency: 0.00016  dbSNP: rs373650093

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171974	SCV000055151	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037361	SCV000061018	uncertain significance	not specified	2013-06-07	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Val1052Met vari ant in LAMA4 has been identified by our laboratory in 1 Sri Lankan individual wi th HCM (LMM unpublished data) and in 1/8600 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Valine (Val) at position 1052 is not conserved in mammals or evolutionarily distant species and one mammal (armadillo) carries a methionine (Met; this variant), suggesting that this change may be tolerated. Additional computational analyses (biochemica l amino acid properties, AlignGVGD, PolyPhen2) also suggest that this variant ma y not impact the protein, though this information is not predictive enough to ru le out pathogenicity. Although collectively this information supports that the V al1052Met variant is more likely benign, additional studies are needed to fully assess its clinical significance.
GeneDx	RCV000037361	SCV000250559	benign	not specified	2016-04-07	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.
Ambry Genetics	RCV000618915	SCV000736740	likely benign	Cardiovascular phenotype	2017-01-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769196	SCV000900572	benign	Cardiomyopathy	2018-07-30	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV001781353	SCV000995756	likely benign	Premature ventricular contraction	2018-11-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001088319	SCV001006951	benign	Dilated cardiomyopathy 1JJ	2024-01-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037361	SCV004038036	likely benign	not specified	2023-08-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745173	SCV005357024	benign	LAMA4-related disorder	2024-04-04	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).