11-47332932-G-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.3372C>A(p.Cys1124Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C1124C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: -0.854

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 11-47332932-G-T is Pathogenic according to our data. Variant chr11-47332932-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 177701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47332932-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.3372C>A	p.Cys1124Ter	stop_gained	31/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3372C>A	p.Cys1124Ter	stop_gained	31/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.3372C>A	p.Cys1124Ter	stop_gained	30/34	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000413 AC: 1 AN: 242086 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 131466

Gnomad AFR exome AF: 0.0000684

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458296 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 725086

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Nonsense variant c.3372C>A in Exon 31 of the MYBPC3 gene that results in the amino acid substitution p.Cys1124* was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 177701]. The observed variant has bene previously reported in patients affected with familial hypertrophic cardiomyopathy (Bashyam, Murali D et al., 2012). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 14, 2023	- -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2022	The p.Cys1124X variant in MYBPC3 has been reported in 1 individual with HCM (Van Driest 2004 PMID: 15519027). This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1124, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, this variant meets our criteria to be classified as pathogenic for autosomal dominant hypertrophic cardiomyopathy (http://pcpgm.partners.org/LMM) based on the predicted impact of the variant. ACMG/AMP criteria applied: PVS1, PM2_P. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 30, 2023	This sequence change creates a premature translational stop signal (p.Cys1124*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 177701). For these reasons, this variant has been classified as Pathogenic. -

Left ventricular noncompaction 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 14, 2023

- -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Dec 14, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 30, 2017

The C1124X variant in the MYBPC3 gene has been reported in association with HCM (Van Driest et al., 2004;Bashyam et al., 2012). Bashyam et al. (2012) describe an Indian boy with HCM at 3-years-old, though hisheterozygous mother and sibling remained asymptomatic. The C1124X variant is predicted to cause loss of normalprotein function either by protein truncation or nonsense-mediated mRNA decay. Other downstream nonsense variantsin the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM (Stensonet al., 2014), indicating that loss of function is a known disease mechanism. Furthermore, this variant is not observedin large population cohorts (Lek et al., 2016). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2021

The p.C1124* pathogenic mutation (also known as c.3372C>A), located in coding exon 31 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 3372. This changes the amino acid from a cysteine to a stop codon within coding exon 31. This alteration has been reported in patients with hypertrophic cardiomyopathy (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10; Bashyam MD et al. Mol Cell Biochem, 2012 Jan;360:373-82; Ko C et al. Genet Med, 2018 01;20:69-75; O'Leary TS et al. J Mol Cell Cardiol, 2019 02;127:165-173). 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	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.34	N
MutationTaster	Benign	1.0	A;A;A
Vest4		0.94
GERP RS		-3.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs727504289; hg19: chr11-47354483;