Submissions for variant NM_000023.4(SGCA):c.662G>A (p.Arg221His)

gnomAD frequency: 0.00027  dbSNP: rs138254713

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000243208	SCV000301552	likely benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000243208	SCV000331580	likely benign	not specified	2017-05-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000665313	SCV000789411	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2017-02-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665313	SCV001021119	benign	Autosomal recessive limb-girdle muscular dystrophy type 2D	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001123794	SCV001282661	likely benign	Sarcoglycanopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genome-Nilou Lab	RCV000665313	SCV001652737	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2021-05-18	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001508812	SCV001715201	uncertain significance	not provided	2020-04-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001508812	SCV001825873	likely benign	not provided	2019-01-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 12746421, 24742800, 19117361)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000243208	SCV002572154	likely benign	not specified	2022-08-19	criteria provided, single submitter	clinical testing	Variant summary: SGCA c.662G>A (p.Arg221His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 251320 control chromosomes, predominantly at a frequency of 0.0071 within the East Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in SGCA causing Limb-Girdle Muscular Dystrophy (LGMD), Autosomal Recessive phenotype (0.002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.662G>A has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy with little evidence for causality and/or in individuals with a very mild phenotype (e.g. Boito_2003, Tian_2015, Yu_2017, Xie_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy. At-least one co-occurrence with another homozygous pathogenic variant have been reported in an individual with LGMD (DYSF exon 5 deletion), providing supporting evidence for a benign role (example, Tian_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments(VUS n=4, likely benign n=3, benign n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Natera, Inc.	RCV000665313	SCV001465522	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2D	2020-04-03	no assertion criteria provided	clinical testing