Submissions for variant NM_003476.5(CSRP3):c.508+18C>T

gnomAD frequency: 0.00332  dbSNP: rs144404101

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183331	SCV000235763	benign	not specified	2014-07-28	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.
PreventionGenetics, part of Exact Sciences	RCV000183331	SCV000309592	benign	not specified		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000183331	SCV001432035	benign	not specified	2020-08-31	criteria provided, single submitter	clinical testing	Variant summary: CSRP3 c.508+18C>T alters a not 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 0.0033 in 143334 control chromosomes, predominantly at a frequency of 0.011 within the African or African-American subpopulation in the gnomAD database (gnomAD v3, genomes dataset), including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 440-fold of the estimated maximal expected allele frequency for a pathogenic variant in CSRP3 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. To our knowledge, no occurrence of c.508+18C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812177	SCV002048482	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Invitae	RCV002054179	SCV002333896	benign	Hypertrophic cardiomyopathy 12; Dilated cardiomyopathy 1M	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004017462	SCV004848981	likely benign	Cardiovascular phenotype	2015-11-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Clinical Genetics, Academic Medical Center	RCV000183331	SCV001921256	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000183331	SCV001929742	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000183331	SCV001970280	benign	not specified		no assertion criteria provided	clinical testing