rs397516061

Positions:

• chr11-47349815-G-A

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.613C>T​(p.Gln205Ter) 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: 32)
• Consequence: MYBPC3 NM_000256.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.80

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 11-47349815-G-A is Pathogenic according to our data. Variant chr11-47349815-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 42774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47349815-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.613C>T	p.Gln205Ter	stop_gained	5/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.613C>T	p.Gln205Ter	stop_gained	5/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.613C>T	p.Gln205Ter	stop_gained	5/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.613C>T	p.Gln205Ter	stop_gained, NMD_transcript_variant	5/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 07, 2019	The p.Gln205X variant in MYBPC3 has been identified in 1 individual with HCM (Alfares 2015) and 1 individual with HCM and ventricular tachycardia (Lu 2018). It was absent from large population studies. This variant has been reported in ClinVar (Variation ID:42774). This nonsense variant leads to a premature termination codon at position 205, which is predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant hypertrophic cardiomyopathy. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon its predicted loss of function impact, identification in affected individuals and absence from controls. ACMG/AMP Criteria applied: PVS1; PM2. -
Pathogenic, no assertion criteria provided	research	Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	-	- -
Pathogenic, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Dec 10, 2019	The MYBPC3 Gln205Ter variant has been reported in 2 HCM probands. It is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified this variant in 1 HCM proband and one affected family member (Ingles et al., 2017). Computational tools CADD and MutationTaster indicate a likely deleterious role. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant results in loss of function of MYBPC3 (PVS1), has been reported in >2 HCM proband (PS4_supporting) and is rare in the general population (PM2), therefore we classify MYBPC3 Gln205Ter as "pathogenic". -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 01, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42774). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685, 30165862). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln205*) 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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 01, 2022

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: 28408708, 27532257, 25611685, 25351510, 31424582, 30681346, 28569743, 30165862) -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 24, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Variants predicted to result in NMD are well-reported in individuals with HCM (ClinVar, PMID: 28771489). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with HCM in ClinVar and the literature (PMID: 25351510, 30165862, 31424582). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2023

The p.Q205* variant (also known as c.613C>T), located in coding exon 5 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 613. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This mutation has been reported in multiple hypertrophic cardiomyopathy (HCM) cohorts, although clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Walsh R et al. Genet. Med., 2017 02;19:192-203; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10; Lu C et al. J Transl Med, 2018 08;16:241). 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	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.88	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.81
GERP RS		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397516061; hg19: chr11-47371366;