rs869025465

Positions:

• chr11-47343546-TGGTCAGCCAGTTCCAC-T

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.1153_1168delGTGGAACTGGCTGACC​(p.Val385fs) 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.94

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 11-47343546-TGGTCAGCCAGTTCCAC-T is Pathogenic according to our data. Variant chr11-47343546-TGGTCAGCCAGTTCCAC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 222706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47343546-TGGTCAGCCAGTTCCAC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1153_1168delGTGGAACTGGCTGACC	p.Val385fs	frameshift_variant	13/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1153_1168delGTGGAACTGGCTGACC	p.Val385fs	frameshift_variant	13/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1153_1168delGTGGAACTGGCTGACC	p.Val385fs	frameshift_variant	12/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1153_1168delGTGGAACTGGCTGACC		non_coding_transcript_exon_variant	13/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PVS1+PM2_Supporting+PS4_Supporting -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 22, 2023

ClinVar contains an entry for this variant (Variation ID: 222706). 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 disrupt the consensus splice site. This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15114369, 28615295). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val385Metfs*16) 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). -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 26, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs869025465; hg19: chr11-47365097;