Submissions for variant NM_000023.4(SGCA):c.929A>G (p.Tyr310Cys)

gnomAD frequency: 0.00016  dbSNP: rs145252144

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000404103	SCV000334021	uncertain significance	not provided	2018-02-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545952	SCV000649784	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2024-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 310 of the SGCA protein (p.Tyr310Cys). This variant is present in population databases (rs145252144, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with SGCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 282511). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SGCA protein function with a positive predictive value of 95%. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000404103	SCV000884508	uncertain significance	not provided	2018-01-22	criteria provided, single submitter	clinical testing	The SGCA c.929A>G; p.Tyr310Cys variant (rs145252144), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with a Finnish population frequency of 0.2% (identified on 45 out of 25,774 chromosomes) and is classified as a variant of unknown significance in ClinVar (ID: 282511). The tyrosine at position 310 is highly conserved and computational analyses of the effects of the p.Tyr310Cys variant on protein structure and function make conflicting predictions (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: probably damaging). Based on the available information, the clinical significance of the p.Tyr310Cys variant cannot be determined with certainty.
Illumina Laboratory Services, Illumina	RCV001123797	SCV001282664	uncertain significance	Sarcoglycanopathy	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	RCV000404103	SCV001755920	uncertain significance	not provided	2021-04-09	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Revvity Omics, Revvity	RCV000545952	SCV003827567	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2020-10-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000545952	SCV003931705	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2023-02-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000545952	SCV002087584	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2020-02-12	no assertion criteria provided	clinical testing