Submissions for variant NM_000023.4(SGCA):c.409G>C (p.Glu137Gln)

dbSNP: rs372210292

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000670049	SCV001211376	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2024-03-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 137 of the SGCA protein (p.Glu137Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SGCA-related conditions (PMID: 28403181, 30703231). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 554420). 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 with a positive predictive value of 95%. This variant disrupts the p.Glu137 amino acid residue in SGCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9192266, 12075495, 19798725, 22095924, 25214167, 26916285). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000670049	SCV002019192	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2021-09-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000670049	SCV002060335	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2021-10-01	criteria provided, single submitter	clinical testing	NM_000023.2(SGCA):c.409G>C(E137Q) is a missense variant classified as a variant of uncertain significance in the context of alpha-sarcoglycanopathy. E137Q has been observed in cases with relevant disease (PMID: 28403181, 30703231). Functional assessments of this variant are not available in the literature. E137Q has not been observed in population frequency databases. In summary, there is insufficient evidence to classify NM_000023.2(SGCA):c.409G>C(E137Q) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155270	SCV003844462	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-02-09	criteria provided, single submitter	clinical testing	Variant summary: SGCA c.409G>C (p.Glu137Gln) results in a 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. Other variants located at this codon have been reported in association with Limb-Girdle Muscular Dystrophy in the HGMD database, supporting a critical relevance of this residue to overall protein function. Specifically, a different variant affecting the same nucleotide and amino acid residue (c.409G>A /p.Glu137Lys) has been associated with Limb-Girdle Muscular Dystrophy (Ding_2019) and is classified pathogenic in ClinVar. The variant was absent in 206116 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.409G>C has been reported as a biallelic compound heterozygous genotype in the literature in at-least two individuals affected with features of Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example: Yu_2017 and Ding_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and pathogenic/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
3billion	RCV000670049	SCV004013489	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.77; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SGCA related disorder (ClinVar ID: VCV000554420 / PMID: 28403181). Different missense changes at the same codon (p.Glu137Gly, p.Glu137Lys) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009438, VCV000286049 / PMID: 9192266). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000670049	SCV004203152	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2024-02-26	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003480755	SCV004224223	likely pathogenic	not provided	2023-05-11	criteria provided, single submitter	clinical testing	PP3, PM2, PM3, PM5
Fulgent Genetics, Fulgent Genetics	RCV000670049	SCV005649536	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2024-06-20	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000670049	SCV005914907	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2023-01-19	criteria provided, single submitter	research
Natera, Inc.	RCV000670049	SCV001453380	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2020-09-16	no assertion criteria provided	clinical testing