rs727504335

Positions:

• chr11-47351291-TG-TCCTC

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PM4_Supporting

The NM_000256.3(MYBPC3):​c.239delinsGAGG​(p.Ala80delinsGlyGly) variant causes a protein altering change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A80A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 protein_altering
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.41

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000256.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000256.3. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.239delinsGAGG	p.Ala80delinsGlyGly	protein_altering_variant	2/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.239delinsGAGG	p.Ala80delinsGlyGly	protein_altering_variant	2/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.239delinsGAGG	p.Ala80delinsGlyGly	protein_altering_variant	2/34	5		A2
MYBPC3	ENST00000544791.1	c.239delinsGAGG	p.Ala80delinsGlyGly	protein_altering_variant, NMD_transcript_variant	2/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 23, 2013

proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 20, 2023

This variant causes an in-frame deletion of one amino acid and insertion of two amino acids at exon 2 of the MYBPC3 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with dilated cardiomyopathy (PMID: 22464770, 27532257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

This variant, c.239delinsGAGG, is a complex sequence change that results in the deletion of 1 and insertion of 2 amino acid(s) in the MYBPC3 protein (p.Ala80delinsGlyGly). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with dilated cardiomyopathy (DCM) (PMID: 22464770, 27532257). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2022

The c.239delCinsGAGG variant (also known as p.A80delinsGG), located in coding exon 2 of the MYBPC3 gene, results from an in-frame deletion of C and insertion of GAGG at nucleotide position 239. This results in the substitution of a highly conserved alanine residue at codon 80 for two glycine residues. This alteration has been detected in an individual from a dilated cardiomyopathy cohort (Lakdawala NK et al. J. Card. Fail., 2012 Apr;18:296-303; Pugh TJ et al. Genet. Med. 2014 Aug;16(8):601-8; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727504335; hg19: chr11-47372843;