Submissions for variant NM_000256.3(MYBPC3):c.926+8C>T

gnomAD frequency: 0.00042  dbSNP: rs377595584

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035680	SCV000059331	likely benign	not specified	2015-04-09	criteria provided, single submitter	clinical testing	c.926+8C>T in intron 11 of MYBPC3: This variant is not expected to have clinical significance because it is not located in the conserved region of the splicing consensus sequence. It has been identified in 33/62508 European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3 77595584).
Invitae	RCV001081892	SCV000558148	likely benign	Hypertrophic cardiomyopathy	2024-01-29	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000625028	SCV000743567	benign	Hypertrophic cardiomyopathy 4	2017-06-27	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625028	SCV000744861	benign	Hypertrophic cardiomyopathy 4	2015-09-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000625028	SCV001265734	uncertain significance	Hypertrophic cardiomyopathy 4	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001108497	SCV001265735	benign	Left ventricular noncompaction 10	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170204	SCV001332756	likely benign	Cardiomyopathy	2023-04-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000457720	SCV001883513	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035680	SCV002765994	likely benign	not specified	2023-11-07	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.926+8C>T alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation 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 0.00071 in 1586860 control chromosomes, predominantly at a frequency of 0.00084 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. This frequency is close the maximum estimated for a pathogenic variant in MYBPC3 suggesting a benign role. c.926+8C>T has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy. These reports do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 23782526). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=7) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV000035680	SCV001925100	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000457720	SCV001959527	likely benign	not provided		no assertion criteria provided	clinical testing