Submissions for variant NM_000256.3(MYBPC3):c.906-7G>T

gnomAD frequency: 0.00036  dbSNP: rs397516079

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035676	SCV000059327	likely benign	not specified	2020-08-12	criteria provided, single submitter	clinical testing	The c.906-7G>T variant in MYBPC3 is classified as likely benign it has been identified in 0.06% (70/122142) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational splice prediction tools as well as in vitro RNA splicing assays do not predict and impact on splicing (Frisso 2016 PMID: 27834932). ACMG/AMP Criteria applied: BS1, BP4, BP7.
GeneDx	RCV000035676	SCV000209459	uncertain significance	not specified	2013-11-20	criteria provided, single submitter	clinical testing	The variant is found in HCM panel(s).
Invitae	RCV001083307	SCV000623627	likely benign	Hypertrophic cardiomyopathy	2024-01-27	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000625029	SCV000743568	likely benign	Hypertrophic cardiomyopathy 4	2016-10-27	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625029	SCV000744862	benign	Hypertrophic cardiomyopathy 4	2017-05-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770373	SCV000901814	likely benign	Cardiomyopathy	2021-06-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000530779	SCV001148282	likely benign	not provided	2020-12-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770373	SCV001357000	likely benign	Cardiomyopathy	2019-11-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035676	SCV002600394	likely benign	not specified	2022-10-10	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.906-7G>T 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. In a mini gene assay, the variant was reported to have no impact on splicing (Frisso_2016). The variant allele was found at a frequency of 0.00028 in 230196 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy (0.00028 vs 0.001), allowing no conclusion about variant significance. c.906-7G>T has been reported in the literature in at least one individual affected with Hypertrophic Cardiomyopathy, without strong evidence for causality (Frisso_2016). This report does not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six submitters classified the variant as likely benign/benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003944892	SCV004766296	likely benign	MYBPC3-related condition	2020-05-05	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).
Clinical Genetics, Academic Medical Center	RCV000035676	SCV001922600	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000530779	SCV001954550	likely benign	not provided		no assertion criteria provided	clinical testing