rs397516072

Variant names:

• chr11-47348423-C-T
• rs397516072
• NM_000256.3:c.772+1G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.772+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: MYBPC3 NM_000256.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.86

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47348423-C-T is Pathogenic according to our data. Variant chr11-47348423-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 42790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47348423-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.772+1G>A		splice_donor_variant, intron_variant	Intron 6 of 34	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.772+1G>A		splice_donor_variant, intron_variant	Intron 6 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.772+1G>A		splice_donor_variant, intron_variant	Intron 6 of 33	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.772+1G>A		splice_donor_variant, intron_variant	Intron 6 of 26	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Nov 11, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Oct 09, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 30, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Hypertrophic cardiomyopathy Pathogenic:2

Jun 10, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Cardiomyopathy Pathogenic:1

Oct 03, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 4 Pathogenic:1

May 01, 2023

Clinical Genomics Laboratory, Stanford Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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] -

Cardiovascular phenotype Pathogenic:1

Jul 27, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.96	D
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397516072; hg19: chr11-47369974; COSMIC: COSV105074700;