Submissions for variant NM_133642.5(LARGE1):c.391G>A (p.Val131Ile)

gnomAD frequency: 0.00027  dbSNP: rs56239539

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724331	SCV000230241	uncertain significance	not provided	2016-01-15	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000178221	SCV000613997	uncertain significance	not specified	2017-02-03	criteria provided, single submitter	clinical testing
Invitae	RCV001087480	SCV000761732	likely benign	Muscular dystrophy-dystroglycanopathy type B6	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000724331	SCV000977894	likely benign	not provided	2020-01-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28454995)
Mayo Clinic Laboratories, Mayo Clinic	RCV000724331	SCV001715619	uncertain significance	not provided	2019-04-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517723	SCV003749853	likely benign	Inborn genetic diseases	2021-06-06	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.
Revvity Omics, Revvity	RCV000724331	SCV003816469	uncertain significance	not provided	2022-02-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000178221	SCV004122813	uncertain significance	not specified	2023-10-12	criteria provided, single submitter	clinical testing	Variant summary: LARGE1 c.391G>A (p.Val131Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00063 in 254490 control chromosomes in the gnomAD database, including 1 homozygotes. c.391G>A has been reported in the literature in an individual affected with Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A who carried a second variant of uncertain significance in the compound heterozygous state. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments including four VUS and three likely benign classifications. Based on the evidence outlined above, the variant was classified as uncertain significance.