rs397516007

Variant names:

• chr11-47333331-T-TG
• rs397516007
• NM_000256.3:c.3192dupC

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.3192dupC​(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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.666

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 11-47333331-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 rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3192dupC	p.Lys1065GlnfsTer12	frameshift_variant, splice_region_variant	Exon 30 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3192dupC	p.Lys1065GlnfsTer12	frameshift_variant, splice_region_variant	Exon 30 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3192dupC	p.Lys1065GlnfsTer12	frameshift_variant, splice_region_variant	Exon 29 of 34	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1419336 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 701598

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.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:4

Dec 16, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 26, 2020

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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' -

Jan 08, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:2

Jul 27, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 20, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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: rs397516007; hg19: chr11-47354882;