rs397515910

Positions:

• chr11-47342627-A-C
• chr11-47342627-A-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.1575T>G​(p.Tyr525Ter) 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYBPC3 NM_000256.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.158

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 11-47342627-A-C is Pathogenic according to our data. Variant chr11-47342627-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47342627-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1575T>G	p.Tyr525Ter	stop_gained	17/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1575T>G	p.Tyr525Ter	stop_gained	17/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.1575T>G	p.Tyr525Ter	stop_gained	16/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.1575T>G	p.Tyr525Ter	stop_gained, NMD_transcript_variant	17/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 27, 2015	The p.Tyr525X variant in MYBPC3 has been reported in one individual with HCM (Bo rtot 2011) and has been identified by our laboratory in one Caucasian individual with HCM. It has not been identified in large population studies. This variant leads to a premature termination codon at position 525, which is predicted to l ead to a truncated or absent protein. Heterozygous loss of function of the MYBPC 3 gene is an established disease mechanism in individuals with HCM. In summary, the p.Tyr525X variant meets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon the predicted impact to the protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 17, 2023	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42547). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 21817903, 30775854). This sequence change creates a premature translational stop signal (p.Tyr525*) 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). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 20, 2024

Identified in patients with HCM in published literature (PMID: 21817903, 30775854, 27532257); at least one patient harbored additional cardiogenetic variants; Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27532257, 21817903, 30775854) -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Mar 26, 2015

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2023

The p.Y525* pathogenic mutation (also known as c.1575T>G), located in coding exon 17 of the MYBPC3 gene, results from a T to G substitution at nucleotide position 1575. This changes the amino acid from a tyrosine to a stop codon within coding exon 17. This mutation has been reported in multiple individuals with HCM (Bortot B et al. Diagn. Mol. Pathol., 2011 Sep;20:175-9; Walsh R et al. Genet. Med., 2017 02;19:192-203; Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Benign	20
DANN	Uncertain	0.98
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.25	N
MutationTaster	Benign	1.0	A;A;A
Vest4		0.95
GERP RS		-3.0

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: rs397515910; hg19: chr11-47364178;