rs397515966

Positions:

• chr11-47337502-G-GA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.2490_2491insT​(p.His831SerfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.0200

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-47337502-G-GA is Pathogenic according to our data. Variant chr11-47337502-G-GA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2490_2491insT	p.His831SerfsTer2	frameshift_variant	25/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2490_2491insT	p.His831SerfsTer2	frameshift_variant	25/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.2490_2491insT	p.His831SerfsTer2	frameshift_variant	24/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.2422_2423insT	p.Ser808PhefsTer7	frameshift_variant, NMD_transcript_variant	25/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249168 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135156

Gnomad AFR exome AF: 0.00

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: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461678 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727128

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2024	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; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.2490_2491insT and S830 fs/1; This variant is associated with the following publications: (PMID: 21839045, 24510615, 29237689, 27532257, 33673806, 31980526, 33190526, 35653365, 34542152, 15519027) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 20, 2018	- -
Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	May 27, 2016	c.2490dupT (p.His831Serfs*2) in the MYBPC3 gene Given the fact that this is a loss of function variant in a gene where loss of function is a well-established mechanism of disease and a moderate amount of case data, we consider this variant to be likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen the variant in an individual with HCM. The variant has been seen in at least 3 unrelated cases of HCM (not including this patient's family). This is moderate case data. It has been reported in 2 cases in the literature. Van Driest et al., 2004 reported the variant using alternative nomenclature (S830 fs/1) in a patient with HCM. Maron et al., 2012 reported the variant in a series of compound heterozygote patients. The patient had HCM and this variant as well as a MYH7 Arg1832Cys variant. This frameshift variant is expected to result in a truncated or absent protein product because of nonsense mediated mRNA decay. Loss of function is an established mechanism of disease in the MYBPC3 gene. The variant was reported online in 3 of 60,340 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 5/26/16). Specifically, the variant was observed in 3 of 33,340 non-Finnish European people. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -

Hypertrophic cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 04, 2015	The p.His831fs variant in MYBPC3 has been observed in at least 4 individuals wit h HCM (Van Driest 2004, Kapplinger 2014, LMM unpublished data) and segregated wi th disease in 1 affected relative (LMM unpublished data). This variant has also been identified in 3/66680 of European chromosomes by the Exome Aggregation Cons ortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397515966). Please note th at for diseases with clinical variability and reduced penetrance, pathogenic var iants may be present at a low frequency in the general population. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequen ce beginning at position 831 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or ab sent protein. Heterozygous loss of function of function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant meets our criter ia to be classified as pathogenic for HCM in an autosomal dominant manner (http: //www.partners.org/personalizedmedicine/LMM) based on the predicted impact of th e variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Dec 16, 2019	ACMG criteria met: PVS1, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change creates a premature translational stop signal (p.His831Serfs*2) 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 present in population databases (rs397515966, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15519027, 21839045). ClinVar contains an entry for this variant (Variation ID: 42625). For these reasons, this variant has been classified as Pathogenic. -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Region Ostergotland

Apr 04, 2022

PVS1, PS4, PP5 -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 01, 2018

Variant summary: MYBPC3 c.2490dupT (p.His831SerfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 246844 control chromosomes. c.2490dupT has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (VanDriest 2004 Maron 2012, Kapplinger 2014, Walsh 2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (3x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397515966; hg19: chr11-47359053;