Submissions for variant NM_000023.4(SGCA):c.541C>T (p.Arg181Cys)

dbSNP: rs574376340

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000733719	SCV000861813	uncertain significance	not provided	2018-06-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804361	SCV000944267	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 181 of the SGCA protein (p.Arg181Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with sarcoglycanopathy (PMID: 12746421). ClinVar contains an entry for this variant (Variation ID: 597557). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SGCA protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222620	SCV002500315	uncertain significance	not specified	2022-03-11	criteria provided, single submitter	clinical testing	Variant summary: SGCA c.541C>T (p.Arg181Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 150906 control chromosomes, predominantly at a frequency of 0.0013 within the Latino subpopulation in the gnomAD database, including 1 homozygote. This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in SGCA causing Autosomal Recessive Limb-Girdle Muscular Dystrophy (0.002), allowing no clear conclusion about variant significance. c.541C>T has been reported in the literature in a compound heterozygous individual who carried a second (likely) pathogenic variant in trans and was affected with muscular dystrophy (Boito_2003). This report does not provide unequivocal conclusions about association of the variant with Autosomal Recessive Limb-Girdle Muscular Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000804361	SCV002776408	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2021-10-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000804361	SCV003827583	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2022-08-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000804361	SCV003931680	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2023-02-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000804361	SCV001453381	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2020-09-16	no assertion criteria provided	clinical testing