ClinVar Miner

Submissions for variant NM_000337.5(SGCD):c.793G>A (p.Val265Ile) (rs772185467)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000730461 SCV000617102 uncertain significance not provided 2018-10-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SGCD gene. The V265I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V265I variant is observed in 23/126454 (0.02%) alleles from individuals of European background (Lek et al., 2016). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000695524 SCV000824030 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2F 2020-08-26 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 265 of the SGCD protein (p.Val265Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs772185467, ExAC 0.02%). This variant has not been reported in the literature in individuals with SGCD-related disease. ClinVar contains an entry for this variant (Variation ID: 449229). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000730461 SCV000858197 uncertain significance not provided 2017-11-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194184 SCV001363522 likely benign not specified 2019-06-24 criteria provided, single submitter clinical testing Variant summary: SGCD c.793G>A (p.Val265Ile) 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 0.00011 in 248936 control chromosomes, predominantly at a frequency of 0.00021 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in SGCD causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.793G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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