rs727503211

Positions:

• chr11-47346331-C-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.966G>A​(p.Trp322*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,476 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.45

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 11-47346331-C-T is Pathogenic according to our data. Variant chr11-47346331-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 164136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47346331-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.966G>A	p.Trp322*	stop_gained	12/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.966G>A	p.Trp322*	stop_gained	12/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.966G>A	p.Trp322*	stop_gained	11/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.966G>A		non_coding_transcript_exon_variant	12/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457476 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724662

Gnomad4 AFR exome AF: 0.0000299

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 14, 2015	The p.Trp322X variant in MYBPC3 has been reported by our laboratory in two indiv iduals with HCM (childhood-onset in one of them). It has not been identified in large population studies. This nonsense variant leads to a premature termination codon at position 322, which is predicted to lead to a truncated or absent prot ein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon the predicted impact of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 23, 2024	This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in individuals with hypertrophic cardiomyopathy or referred for MYBPC3 genetic testing (PMID: 27532257, 25611685, 38002985, 37089884). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 16, 2024	This sequence change creates a premature translational stop signal (p.Trp322*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25611685; internal data). ClinVar contains an entry for this variant (Variation ID: 164136). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2024	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, 38002985, 37652022, 25611685, 37089884) -
Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 16, 2016	p.Trp322X (c.966G>A) in exon 12 of the MYBPC3 gene (NM_000256.3) We have seen this variant in a person with HCM. Testing was performed by Invitae. Truncating variants are an established mechanism of disease for this gene. Therefore, we consider this variant to be very likely disease-causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There is weak case data for this variant, which has been seen in at least 2 unrelated cases of HCM (not including this patient's family). The variant has not been reported in the literature. It is also listed on cardiodb.org as present in the cohort of OMGL/LMM HCM cohort, classified as pathogenic. There is no variation at codon 322 listed in the Exome Aggregation Consortium dataset (ExAC; http://exac.broadinstitute.org/), which includes variant calls on ~64,000 unrelated individuals of African, Asian, European, and Latino descent or the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in ExAC is mean 24x, median 19x, and >90% of people have 10x coverage. The average coverage at that site in gnomAD is median ~25x, mean ~30x, and >90% of people have 10x coverage. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2024

The p.W322* pathogenic mutation (also known as c.966G>A), located in coding exon 12 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 966. This changes the amino acid from a tryptophan to a stop codon within coding exon 12. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Alfares AA et al. Genet. Med., 2015 Nov;17:880-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.83
GERP RS		4.7

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: rs727503211; hg19: chr11-47367882;