Submissions for variant NM_000426.4(LAMA2):c.6128A>G (p.Gln2043Arg)

gnomAD frequency: 0.00063  dbSNP: rs144155507

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224036	SCV000280813	uncertain significance	not provided	2015-12-23	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Illumina Laboratory Services, Illumina	RCV000341200	SCV000460056	uncertain significance	Congenital muscular dystrophy due to partial LAMA2 deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000224036	SCV000618096	likely benign	not provided	2018-07-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535681	SCV000658729	likely benign	LAMA2-related muscular dystrophy	2025-01-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000224036	SCV001714795	uncertain significance	not provided	2023-05-12	criteria provided, single submitter	clinical testing	BP4
Revvity Omics, Revvity	RCV000224036	SCV003816362	likely benign	not provided	2023-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000522850	SCV003922658	uncertain significance	not specified	2023-03-29	criteria provided, single submitter	clinical testing	Variant summary: LAMA2 c.6128A>G (p.Gln2043Arg) results in a conservative amino acid change located in the Laminin domain II (IPR010307) of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 250812 control chromosomes (including 1 homozygote), predominantly at a frequency of 0.00092 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in LAMA2 causing Laminin Alpha 2-Related Dystrophy (0.00053 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.6128A>G in individuals affected with Laminin Alpha 2-Related Dystrophy and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000522850	SCV000804876	uncertain significance	not specified	2017-06-20	no assertion criteria provided	clinical testing