rs397515933

chr11-47341142-GA-G

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.1892del(p.Phe631SerfsTer32) variant causes a frameshift change involving the alteration of a conserved nucleotide. 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. F631F) 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: 8.89

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 11-47341142-GA-G is Pathogenic according to our data. Variant chr11-47341142-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 42580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47341142-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1892del	p.Phe631SerfsTer32	frameshift_variant	19/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1892del	p.Phe631SerfsTer32	frameshift_variant	19/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1892del	p.Phe631SerfsTer32	frameshift_variant	18/34	5		A2
MYBPC3	ENST00000544791.1	c.1892del	p.Phe631SerfsTer32	frameshift_variant, NMD_transcript_variant	19/27	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 06, 2017

The c.1892delT pathogenic variant in the MYBPC3 gene has been reported in association with hypertrophic cardiomyopathy (HCM) (Ho et al., 2017; Walsh et al., 2017). Furthermore, this variant has been classified as a pathogenic variant by another clinical laboratory in ClinVar (SCV000059096.4; Landrum et al., 2016). This variant causes a shift in reading frame starting at codon phenylalanine 631, changing it to a serine, and creating a premature stop codon at position 32 of the new reading frame, denoted p.Phe631SerfsX32. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the MYBPC3 gene have been reported in Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.1892delT variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 27, 2011

The Phe631fs variant has not been previously reported, but has been identified i n 1 individual with HCM out of >1950 Caucasian probands (>3900 chromosomes) test ed by our laboratory. This low frequency is consistent with a pathogenic role. T his variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 631 and leads to a premature stop codon 32 ami no acids downstream. This alteration is then predicted to lead to a truncated or absent protein (loss-of-function). Loss-of-function of the MYBPC gene is an est ablished disease mechanism and typically leads to HCM, which is consistent with the phenotype of the proband tested by our laboratory. Therefore, this variant m eets our criteria for pathogenicity based on low frequency and predicted impact on the protein (http://pcpgm.partners.org/LMM). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs397515933; hg19: chr11-47362693;