11-47343064-G-T

Variant names:

• chr11-47343064-G-T
• NM_000256.3:c.1308C>A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.1308C>A​(p.Cys436*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.824

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 19 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-47343064-G-T is Pathogenic according to our data. Variant chr11-47343064-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1769560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1308C>A	p.Cys436*	stop_gained	Exon 15 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1308C>A	p.Cys436*	stop_gained	Exon 15 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1308C>A	p.Cys436*	stop_gained	Exon 14 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1308C>A		non_coding_transcript_exon_variant	Exon 15 of 27	5		ENSP00000444259.1

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:1

Oct 03, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in MYBPC3 is a nonsense variant predicted to create a premature stop codon, p.(Cys436*), in biologically relevant exon 15/35 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 7493026, 9048664, 9562578, 17823372, 19574547, 18337725). Loss-of-function variants are a well-established cause of disease in exon 15 (ClinVar). This variant is absent from the population database gnomAD v4.1. This variant has been reported in at least two unrelated individuals with hypertrophic cardiomyopathy (PMID: 23233322, Royal Melbourne Hospital). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM2_Supporting, PM5_Supporting, PS4_Supporting -

Cardiovascular phenotype Pathogenic:1

Aug 03, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C436* pathogenic mutation (also known as c.1308C>A), located in coding exon 15 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 1308. This changes the amino acid from a cysteine to a stop codon within coding exon 15. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Kassem HSh et al. J Cardiovasc Transl Res, 2013 Feb;6:65-80). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.41	N
Vest4		0.84
GERP RS		-0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.75		Position offset: 4
DS_DL_spliceai		0.29		Position offset: -43

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-47364615;