rs397515979

chr11-47336003-TG-Tchr11-47336003-TG-TGG

Variant summary

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

The NM_000256.3(MYBPC3):c.2610del(p.Ser871AlafsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,366,506 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. PS870Q?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.292

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 11-47336003-TG-T is Pathogenic according to our data. Variant chr11-47336003-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47336003-TG-T is described in Lovd as [Pathogenic]. Variant chr11-47336003-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2610del	p.Ser871AlafsTer8	frameshift_variant	26/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2610del	p.Ser871AlafsTer8	frameshift_variant	26/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2610del	p.Ser871AlafsTer8	frameshift_variant	25/34	5		A2
MYBPC3	ENST00000544791.1	c.*115del		3_prime_UTR_variant, NMD_transcript_variant	26/27	5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000146 AC: 20 AN: 1366506 Hom.: 0 Cov.: 33 AF XY: 0.0000149 AC XY: 10 AN XY: 670898

Gnomad4 AFR exome AF: 0.0000331

Gnomad4 AMR exome AF: 0.0000871

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000283

Gnomad4 FIN exome AF: 0.0000199

Gnomad4 NFE exome AF: 0.0000113

Gnomad4 OTH exome AF: 0.0000178

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Ser871AlafsX8 variant in MYBPC3 has been reported in at least 6 individuals with hypertrophic cardiomyopathy (Kaski 2009, Walsh 2017, Cecconi 2016). It was also identified in 11/168356 chromosomes by gnomAD (https://gnomad.broadinstitute.org); however, average read depth at this location was low, so the reliability of this data is unclear. The variant has also been reported in ClinVar (Variation ID 181083). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 871 and leads to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PVS1. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 08, 2023	This sequence change creates a premature translational stop signal (p.Ser871Alafs*8) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20031618, 27532257, 27600940). This variant is also known as P870fs878X. ClinVar contains an entry for this variant (Variation ID: 181083). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 05, 2019

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 21, 2020

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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20031618, 27532257, 25351510, 27600940, 31513939) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs397515979; hg19: chr11-47357554;