rs730880723

chr11-47346212-C-CT

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.1084_1085insA(p.Ser362LysfsTer28) 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. S362S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.63

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 11-47346212-C-CT is Pathogenic according to our data. Variant chr11-47346212-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 181159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1084_1085insA	p.Ser362LysfsTer28	frameshift_variant	12/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1084_1085insA	p.Ser362LysfsTer28	frameshift_variant	12/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1084_1085insA	p.Ser362LysfsTer28	frameshift_variant	11/34	5		A2
MYBPC3	ENST00000544791.1	c.1084_1085insA	p.Ser362LysfsTer28	frameshift_variant, NMD_transcript_variant	12/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 15, 2013	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ser362LysX28 (c.1084dupA) in the MYBPC3 gene. Given the strong evidence that frameshift variants in MYBPC3 are disease-causing we consider this variant likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant appears to be novel. This is a frame-shifting variant that creates a premature stop codon 5 codons downstream of the variant. The variant is expected to either cause a truncated protein or a completely absent protein due to nonsense-mediated mRNA decay. While this specific variant is novel, many other frameshift and null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). Furthermore, these types of variants in MYBPC3 are only very rarely seen in individuals without cardiomyopathy (Pan et al 2012). The variant is not listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of June 18, 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2015	The c.1084dupA pathogenic variant in the MYBPC3 gene been reported previously in one individual with HCM, and was absent from 307 control alleles (Wang J et al., 2014). Additionally, the c.1084dupA mutation was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant causes a shift in reading frame starting at codon Serine 362, changing it to a Lysine, and creating a premature stop codon at position 28 of the new reading frame, denoted p.Ser362LysfsX28. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Furthermore, other frameshift variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM and dilated cardiomyopathy (DCM) (Stenson P et al., 2014). -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2016

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MYBPC3 are known to be pathogenic. This particular variant has been reported in the literature in an individual affected with hypertrophic cardiomyopathy (PMID: 25132132). This variant is also known as 1084_1085insA in the literature. This sequence change inserts 1 nucleotide in exon 12 of the MYBPC3 mRNA (c.1084dupA), causing a frameshift at codon 362. This creates a premature translational stop signal (p.Ser362Lysfs*28) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs730880723; hg19: chr11-47367763;