rs886037900

chr11-47342882-GC-G

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.1404del(p.Gln469SerfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,646 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G468G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: -3.19

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 11-47342882-GC-G is Pathogenic according to our data. Variant chr11-47342882-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 254153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47342882-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1404del	p.Gln469SerfsTer19	frameshift_variant	16/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1404del	p.Gln469SerfsTer19	frameshift_variant	16/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1404del	p.Gln469SerfsTer19	frameshift_variant	15/34	5		A2
MYBPC3	ENST00000544791.1	c.1404del	p.Gln469SerfsTer19	frameshift_variant, NMD_transcript_variant	16/27	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460646 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726516

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2019	Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 254153; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); 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: 31513939, 27532257, 27476098) -

Isolated Noncompaction of the Ventricular Myocardium Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Loeys Lab, Universiteit Antwerpen

Feb 26, 2021

This sequence change results in a frameshift variant in the MYBPC3 predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay , which is a known mechanism for HCM (PVS1). This variant is absent from population databases such as GnomAD (PM2). This variant has not been reported in the literature. This variant is known in clinvar as pathogenic (PP5). We identified this variant in a LVNC patient with a family history of HCM and 9 other patients with HCM. In 8 families the variant co-segregated with cardiomyopathy (in total 27 individuals) PP1strong. In conclusion this variant was classified as a pathogenic variant according to ACMG-guidelines (PVS1; PM2;PP1strong;PP5). -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Medical Genetics Ghent, University of Ghent

Jan 01, 2016

This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server) and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Human Genetics, University of Leuven

Oct 31, 2018

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 05, 2024

The c.1404delG pathogenic mutation, located in coding exon 16 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 1404, causing a translational frameshift with a predicted alternate stop codon (p.Q469Sfs*19). This alteration has been reported in hypertrophic cardiomyopathy cohorts (Walsh R et al. Genet Med, 2017 Feb;19:192-203; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754; Bourfiss M et al. Circ Genom Precis Med, 2022 Dec;15:e003704). 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

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: rs886037900; hg19: chr11-47364433;