Submissions for variant NM_000256.3(MYBPC3):c.1897+1G>A

dbSNP: rs397515935

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000539201	SCV000059098	pathogenic	Hypertrophic cardiomyopathy	2017-11-06	criteria provided, single submitter	clinical testing	The c.1897+1G>A variant in MYBPC3 has been identified by our laboratory in 3 ind ividuals with HCM and segregated with disease in 1 affected relative. It was abs ent from large population studies. This variant has been reported in ClinVar (Va riation ID:42582). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Splice site and other MYBPC3 variants resulting i n a heterozygous loss of function are strongly associated with HCM. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosom al dominant manner based upon its predicted loss of function impact, identificat ion in affected individuals, segregation with disease, and absence from controls . ACMG/AMP Criteria applied: PVS1; PM2; PS4_Supporting (Richards 2015).
GeneDx	RCV000158128	SCV000208063	pathogenic	not provided	2021-04-28	criteria provided, single submitter	clinical testing	Identified in multiple individuals with HCM referred for genetic testing at GeneDx and in published literature (Alfares et al., 2015; Walsh et al., 2017); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID#42582; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25611685, 27532257, 33673806)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000539201	SCV000623538	pathogenic	Hypertrophic cardiomyopathy	2024-11-07	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 19 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25611685, 27532257). ClinVar contains an entry for this variant (Variation ID: 42582). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000158128	SCV000748027	pathogenic	not provided	2016-04-14	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000158128	SCV000928039	pathogenic	not provided	2018-11-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004984654	SCV005458017	likely pathogenic	Cardiovascular phenotype	2024-07-12	criteria provided, single submitter	clinical testing	The c.1897+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 19 of the MYBPC3 gene. This variant has been reported in association with hypertrophic cardiomyopathy (HCM) (Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Ware SM et al. J Am Heart Assoc, 2021 May;10:e017731; Hathaway J et al. BMC Cardiovasc Disord, 2021 Mar;21:126). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel 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 likely pathogenic.