rs397515896

chr11-47343061-CA-C

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.1310del(p.Val437GlyfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V437V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.67

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: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47343061-CA-C is Pathogenic according to our data. Variant chr11-47343061-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 42522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47343061-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1310del	p.Val437GlyfsTer13	frameshift_variant	15/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1310del	p.Val437GlyfsTer13	frameshift_variant	15/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1310del	p.Val437GlyfsTer13	frameshift_variant	14/34	5		A2
MYBPC3	ENST00000544791.1	c.1310del	p.Val437GlyfsTer13	frameshift_variant, NMD_transcript_variant	15/27	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 17, 2011	The Val437fs variant has been reported in 1 individual with HCM and was absent f rom 200 control chromosomes (Richard 2003). In addition, this variant has not be en previously identified in over 3300 Caucasian chromosomes tested by our labora tory. This low frequency increases the likelihood that this variant is disease c ausing. Furthermore, the Val437fs variant is predicted to cause a frameshift, w hich alters the protein's amino acid sequence beginning at codon 437 and leads t o a premature stop codon 13 amino acids downstream. This alteration is then pred icted to lead to a truncated or absent protein. Loss of function is an establish ed mechanism of disease for the MYBPC3 gene, which makes it highly likely that t he Val437fs variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 09, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 42522). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12707239). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val437Glyfs*13) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515896; hg19: chr11-47364612;