Submissions for variant NM_000256.3(MYBPC3):c.3190+2T>G

gnomAD frequency: 0.00001  dbSNP: rs113358486

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000529897	SCV000059214	pathogenic	Hypertrophic cardiomyopathy	2018-06-04	criteria provided, single submitter	clinical testing	The c.3190+2T>G variant in MYBPC3 has been reported in at least 15 individuals w ith HCM and segregated with disease in 3 affected relatives from 2 families (Ber ge 2014, Walsh 2016, LMM data). It has also been identified in 2/111408 of Europ ean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org; dbSNP rs113358486). This variant occurs in the invariant region (+ /- 1,2) of the splice consensus sequence and is predicted to cause altered splic ing leading to an abnormal or absent protein. Heterozygous loss of function of t he MYBPC3 gene is an established disease mechanism in HCM. In summary, this vari ant meets criteria to be classified as pathogenic for HCM in an autosomal domina nt manner based upon predicted splicing impact, case observations, and segregati on studies. ACMG/AMP criteria applied: PVS1, PS4, PM2, PP1.
Blueprint Genetics	RCV000035564	SCV000207065	pathogenic	Primary familial hypertrophic cardiomyopathy	2015-11-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000158220	SCV000208155	pathogenic	not provided	2022-03-16	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27532257, 23690394, 26914223, 24111713, 29121657, 33673806)
Invitae	RCV000529897	SCV000623584	pathogenic	Hypertrophic cardiomyopathy	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 29 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (rs113358486, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24111713, 26914223, 27532257). ClinVar contains an entry for this variant (Variation ID: 42691). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000619688	SCV000737350	pathogenic	Cardiovascular phenotype	2022-02-25	criteria provided, single submitter	clinical testing	The c.3190+2T>G intronic pathogenic mutation results from a T to G substitution two nucleotides after coding exon 29 in the MYBPC3 gene. This alteration has been detected in multiple individuals from cohorts reported to have hypertrophic cardiomyopathy (HCM) and in individuals referred for HCM genetic testing (Berge KE et al. Clin Genet. 2014;86(4):355-60; Walsh R et al. Genet Med. 2017 02;19(2):192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV001176798	SCV001340853	pathogenic	Cardiomyopathy	2021-01-05	criteria provided, single submitter	clinical testing	This variant causes a T to G nucleotide substitution at the +2 position of intron 29 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 26914223, 27532257, 28971120). This variant has been identified in 2/239022 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Clinical Genetics Laboratory, Region Ostergotland	RCV001731477	SCV001984992	pathogenic	Hypertrophic cardiomyopathy 4	2020-12-02	criteria provided, single submitter	clinical testing	PVS1, PS4, PP3, PP5, BP2
Fulgent Genetics, Fulgent Genetics	RCV002477068	SCV002779710	pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2022-04-09	criteria provided, single submitter	clinical testing