ClinVar Miner

Submissions for variant NM_000337.5(SGCD):c.699+13_699+15del (rs397517924)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172589 SCV000055144 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041410 SCV000065105 benign not specified 2012-11-28 criteria provided, single submitter clinical testing Lys238del in exon 8 of SGCD: This variant has been reported in a heterozygous st ate in two individuals with apparently sporadic DCM and was not detected in 400 non-race matched control chromosomes (Tsubata 2000). This study also showed that the Lys238del variant led to reduced SGCD protein in cell culture experiments. However, we have detected the Lys238del variant in 3% (10/334) of healthy Black control chromosomes (LMM unpublished data). In addition, this variant has been i dentified in 2.1% (79/3782) of African American chromosomes from a broad populat ion by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/).
PreventionGenetics,PreventionGenetics RCV000041410 SCV000303688 benign not specified criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000041410 SCV000331869 benign not specified 2015-08-21 criteria provided, single submitter clinical testing
Invitae RCV000987624 SCV000562855 benign Autosomal recessive limb-girdle muscular dystrophy type 2F 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000041410 SCV000565560 benign not specified 2015-10-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000172589 SCV000610950 likely benign not provided 2017-08-28 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000172589 SCV000843829 likely benign not provided 2018-02-14 criteria provided, single submitter clinical testing
Mendelics RCV000987624 SCV001137015 benign Autosomal recessive limb-girdle muscular dystrophy type 2F 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000041410 SCV001338638 benign not specified 2020-04-13 criteria provided, single submitter clinical testing Variant summary: SGCD c.699+13_699+15delAAG alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0015 in 222898 control chromosomes, predominantly at a frequency of 0.023 within the African or African-American subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 920-fold 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 African or African-American origin. c.699+13_699+15delAAG has been reported in the literature in individuals affected with Cardiomyopathy (examples- Tsubata_2000, Norton_2012, Pugh_2014). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=4)/likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign.

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