Variant 11-47333331-T-TG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000256.3(MYBPC3):c.3192_3193insC(p.Lys1065GlnfsTer12) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,419,336 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.666

Variant links:

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]

MYBPC3 links:

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ACMG classification

Classification made for transcript

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 11-47333331-T-TG is Pathogenic according to our data. Variant chr11-47333331-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 42693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.3192_3193insC	p.Lys1065GlnfsTer12	frameshift_variant, splice_region_variant	30/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.3192_3193insC	p.Lys1065GlnfsTer12	frameshift_variant, splice_region_variant	30/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.3192_3193insC	p.Lys1065GlnfsTer12	frameshift_variant, splice_region_variant	29/34	5		A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.05e-7

AC:

AN:

1419336

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701598

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

9.19e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 16, 2014	The p.Lys1065fs variant in MYBPC3 has been reported in at least 4 individuals wi th HCM and segregated with disease in 2 affected relatives from 1 family (Girola mi 2006, Girolami 2010, Olivotto 2011, Witjas-Paalberends 2013; note that th ese manuscripts contain overlapping cohorts). This variant has also been identif ied by our laboratory in 3 individuals with HCM. Data from large population stud ies is insufficient to assess the frequency of this variant. The p.Lys1065fs var iant is predicted to cause a frameshift, which alters the protein?s amino acid s equence beginning at position 1065 and leads to a premature termination codon 12 amino acids downstream. This alteration is then predicted to lead to a truncate d or absent protein. Heterozygous loss-of-function of the MYBPC3 gene is an esta blished disease mechanism in individuals with HCM. In summary, this variant meet s our criteria to be classified as pathogenic for HCM in an autosomal dominant m anner (http://www.partners.org/personalizedmedicine/LMM). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Lys1065Glnfs*12) 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 HCM (PMID: 11499719, 16858239, 20359594, 23674513, 27483260, 28408708). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42693). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This variant inserts 1 nucleotide in exon 30 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 16858239, 20031618, 20173211, 20359594, 21302287, 21835320, 23674513, 25524337, 25611685, 25740977, 26656175, 27483260, 27532257, 28408708, 28615295, 28790153, 29121657, 29710196, 29875424, 30297972, 30550750, 32228044, 32481709, 32841044, 34556856). One of these individuals also carried an additional likely pathogenic variant in the same gene (PMID: 27483260). This variant has also been reported in one individual affected with sudden cardiac death (PMID: 26688388). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Feb 26, 2020	This MYBPC3 Lys1065fs is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/) and has been identified in multiple unrelated HCM cases (see references). We have identified the this variant in one HCM patient. Familial segregation revealed an affected 3rd degree relative also carried this variant. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant results in loss of function of MYBPC3 (PVS1), is rare in the general population (PM2) and has been identified in at least 10 probands (PS4_moderate), therefore we classify MYBPC3 Lys1065fs as 'pathogenic' -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2022	Segregated with the p.(P371R) missense variant on the same allele (in cis) in multiple affected relatives from one family with HCM (Girolami et al., 2010); Not observed in large population cohorts (gnomAD); Frameshift 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: 32686758, 21302287, 21835320, 23674513, 16858239, 27600940, 28408708, 25740977, 27532257, 29121657, 26656175, 18533079, 29710196, 30550750, 20173211, 20031618, 20359594) -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2021

The c.3192dupC pathogenic mutation, located in coding exon 30 of the MYBPC3 gene, results from a duplication of C at nucleotide position 3192, causing a translational frameshift with a predicted alternate stop codon (p.K1065Qfs*12). This alteration (also referred to as insC1065, K1065fs, and c.3192-3193insC in the literature) has been reported in several individuals with hypertrophic cardiomyopathy (HCM) (Girolami F et al. J Cardiovasc Med (Hagerstown). 2006;7(8):601-7; Roncarati R et al. J Cell Physiol. 2011;226(11):2894-900; Witjas-Paalberends ER et al. Cardiovasc Res. 2013;99(3):432-41; Ingles J et al. Circ Cardiovasc Genet. 2017;10(2)), and has been reported to segregate with disease in families (Girolami F et al. J Am Coll Cardiol. 2010;55(14):1444-53; Ross SB et al. Circ Cardiovasc Genet. 2017 Jun;10(3)). 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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over