Submissions for variant NM_000231.3(SGCG):c.392A>G (p.Lys131Arg)

gnomAD frequency: 0.00001  dbSNP: rs544414698

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001111147	SCV001268663	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856478	SCV002285975	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2C	2021-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces lysine with arginine at codon 131 of the SGCG protein (p.Lys131Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs544414698, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with SGCG-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Revvity Omics, Revvity	RCV001856478	SCV003819955	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2C	2021-12-17	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001856478	SCV004048519	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2C		criteria provided, single submitter	clinical testing	The missense variant p.K131R in SGCG (NM_000231.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.K131R variant is observed in 2/30,606 (0.0065%) alleles from individuals of South Asian background in gnomAD Exomes and in 1/978 (0.1022%) alleles from individuals of South Asian background in 1000 Genomes. There is a small physicochemical difference between lysine and arginine, which is not likely to impact secondary protein structure as these residues share similar properties. The variant is predicted to be damaging by SIFT and the residue is conserved across species. The amino acid change p.Lys131Arg in SGCG is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.