Submissions for variant NM_000256.3(MYBPC3):c.772+1G>A

dbSNP: rs397516072

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000204012	SCV000059317	pathogenic	Hypertrophic cardiomyopathy	2011-06-10	criteria provided, single submitter	clinical testing	The 772+1G>A variant has been identified in four HCM probands (2 cases in Erdman 2001 - reported as IVS7+1G>A and 2 cases in our laboratory). One of these proba nds had a family history of HCM and the variant segregated with disease in three additional affected family members. This variant alters the highly conserved -1 splicing position, and has been shown to result in the skipping of exon 7 or ex ons 7 and 8, both of which cause a frame shift and a premature termination signa l (Erdmann 2001). In summary, this data meets our criteria to classify this vari ant as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204012	SCV000261645	pathogenic	Hypertrophic cardiomyopathy	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 6 of the MYBPC3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 11499719). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42790). Studies have shown that disruption of this splice site results in skipping of exon 6 and exons 6 and 7, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 11499719). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000250001	SCV000318796	pathogenic	Cardiovascular phenotype	2022-07-27	criteria provided, single submitter	clinical testing	The c.772+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 6 of the MYBPC3 gene. This alteration (also referred to as IVS7+1G>A) has been reported in subjects with hypertrophic cardiomyopathy (HCM) and was shown to segregate with disease in one family (Erdmann J et al. J. Am. Coll. Cardiol., 2001 Aug;38:322-30; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Walsh R et al. Genet. Med., 2017 02;19:192-203). This alteration has also been reported to impact mRNA splicing (Erdmann J et al. J. Am. Coll. Cardiol., 2001 Aug;38:322-30). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001781348	SCV001470942	pathogenic	not provided	2019-11-11	criteria provided, single submitter	clinical testing	The MYBPC3 c.772+1G>A variant (rs397516072), also published as IVS7+1G>A, is reported in the literature in multiple individuals affected with hypertrophic cardiomyopathy (Erdmann 2001, Walsh 2017). In one family, this variant was observed to segregate with disease in all affected members (Erdmann 2001). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice donor site of intron 6, which is likely to disrupt gene function. Indeed, RNA analyses of individuals with this variant exhibit skipping of exon 6 or exons 6 and 7 (Erdmann 2001). Based on available information, this variant is considered to be pathogenic. References: Erdmann J et al. Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2001 Aug;38(2):322-30. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203.
Revvity Omics, Revvity	RCV001781348	SCV002017655	pathogenic	not provided	2019-10-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486552	SCV004239392	pathogenic	Cardiomyopathy	2022-10-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001781348	SCV005080217	pathogenic	not provided	2024-04-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published RNA studies using patient lymphocytes show that this variant causes abnormal splicing, resulting in aberrant transcripts showing either the skipping of exon 6 or exons 6 and 7, which leads to frameshift events (PMID: 11499719); Published functional studies using a zebrafish model show that this variant causes impaired cardiac function and recapitulates features of a human HCM phenotype (PMID: 31943169); 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; Also denoted as IVS7+1G>A due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 25611685, 27532257, 29398688, 11499719, 31943169)
Clinical Genomics Laboratory, Stanford Medicine	RCV005208121	SCV005849638	pathogenic	Hypertrophic cardiomyopathy 4	2023-05-01	criteria provided, single submitter	clinical testing	The c.772+1G>A variant in the MYBPC3 gene has been previously reported in at least 6 unrelated individual with hypertrophic cardiomyopathy and co-segregated with disease in 3 affected relatives (Alfares et al., 2015; Erdmann et al., 2001; Teramoto et al., 2018; Walsh et al., 2017; Zhao et al., 2022) This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 42790). This variant alters the canonical donor splice site in intron 6, which is predicted to result in abnormal gene splicing. Heterozygous loss of function is an established mechanism of disease for the MYBPC3 gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.772+1G>A variant as pathogenic for autosomal dominant hypertrophic cardiomyopathy based on the information above. [ACMG evidence codes used: PVS1; PS4_Moderate; PM2; PP1]