rs397515931

Positions:

• chr11-47341171-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000256.3(MYBPC3):​c.1863delC​(p.Phe621fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.0190

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 12 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 11-47341171-CG-C is Pathogenic according to our data. Variant chr11-47341171-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 42578.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-47341171-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1863delC	p.Phe621fs	frameshift_variant	19/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1863delC	p.Phe621fs	frameshift_variant	19/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1863delC	p.Phe621fs	frameshift_variant	18/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1863delC		non_coding_transcript_exon_variant	19/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 09, 2015

The p.Phe621fs variant in MYBPC3 has been identified by our laboratory in 2 adul ts with HCM and segregated with disease in 1 affected family member. It was abse nt from large population studies (dbSNP rs397515931). This frameshift variant is predicted to alter the protein's amino acid sequence beginning at position 621 and lead to a premature termination codon 42 amino acids downstream. This altera tion is then predicted to lead to a truncated or absent protein. Heterozygous lo ss of MYBPC3 function is an established disease mechanism in HCM. In summary, th is variant meets our criteria to be classified as pathogenic (http://www.partner s.org/personalizedmedicine/LMM) for HCM in an autosomal dominant manner based up on the predicted impact of the variant and absence from controls. -

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: rs397515931; hg19: chr11-47362722;