Submissions for variant NM_000337.6(SGCD):c.848A>G (p.Gln283Arg)

gnomAD frequency: 0.00019  dbSNP: rs397516338

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172107	SCV000051050	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036266	SCV000059918	likely benign	not specified	2014-11-25	criteria provided, single submitter	clinical testing	p.Gln283Arg in exon 9 of SGCD: This variant is not expected to have clinical sig nificance because it has been identified in 0.6% (57/8734) of East Asian chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516338).
Illumina Laboratory Services, Illumina	RCV000404763	SCV000455500	likely benign	Limb-girdle muscular dystrophy, recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000365095	SCV000455502	likely benign	Qualitative or quantitative defects of delta-sarcoglycan	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV001084187	SCV000638182	likely benign	Autosomal recessive limb-girdle muscular dystrophy type 2F	2024-01-29	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000584814	SCV000692523	likely benign	Hypertrophic cardiomyopathy 1	2017-03-16	criteria provided, single submitter	research	The SGCD Gln283Arg variant is present at high frequency in the Exome Aggregation Consortium dataset and is particularly common in the East Asian population; allele frequency=0.006379 (MAF= 0.0004690, http://exac.broadinstitute.org/). We identified SGCD Gln283Arg in 1 HCM proband with no family history of HCM or SCD. Computational tools PolyPhen-2 and MutationTaster predict the amino acid substitution to be "probably damaging" and "disease-causing" respectively, however SIFT predicts this variant to be "tolerated". In summary, based on the current literature, our limited understanding of the role of SGCD in HCM, and an allele frequency higher than expected for HCM, we classify SGCD Gln283Arg as "likely benign".
Genetics and Genomics Program, Sidra Medicine	RCV001293129	SCV001434119	likely benign	Primary dilated cardiomyopathy		criteria provided, single submitter	research
GeneDx	RCV000172107	SCV001818906	likely benign	not provided	2019-10-28	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32344918, 26720722, 23861362, 27707468)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036266	SCV002555818	likely benign	not specified	2022-06-10	criteria provided, single submitter	clinical testing	Variant summary: SGCD c.848A>G (p.Gln283Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00056 in 248152 control chromosomes (gnomAD), predominantly at a frequency of 0.0076 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in SGCD causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.00072), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.848A>G in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive has been reported. One publication has found that the variant protein interacts with other SGC proteins in an identical manner as wild-type, although there is reduced cell surface expression of the complete SGC complex (Chen_2015). Five ClinVar submitters have assessed the variant since 2014: all five classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000172107	SCV004237244	uncertain significance	not provided	2023-03-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944896	SCV004763148	likely benign	SGCD-related disorder	2020-12-17	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).