rs1064793202

Positions:

• chr11-47333622-G-GTT

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.3124_3125insAA​(p.Thr1042LysfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.441

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 11-47333622-G-GTT is Pathogenic according to our data. Variant chr11-47333622-G-GTT is described in ClinVar as [Pathogenic]. Clinvar id is 418356.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.3124_3125insAA	p.Thr1042LysfsTer5	frameshift_variant	29/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3124_3125insAA	p.Thr1042LysfsTer5	frameshift_variant	29/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.3124_3125insAA	p.Thr1042LysfsTer5	frameshift_variant	28/34	5		ENSP00000382193	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2019	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); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID 418356; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 15519027, 9562578, 26914223) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 418356). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) (PMID: 9562578, 26914223). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr1042Lysfs*5) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 18, 2016	The p.Thr1042fs variant in MYBPC3 has been reported in 1 individual with HCM and segregated with disease in 5 affected relatives (Niimura 1998). It was absent f rom large population studies, though the ability of these studies to accurately detect indels may be limited. This variant is predicted to cause a frameshift, w hich alters the protein?s amino acid sequence beginning at position 1042 and lea ds to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss-of-f unction variants are strongly associated with HCM. In summary, this variant meet s criteria to be classified as pathogenic for HCM in an autosomal dominant manne r based upon segregation studies and predicted impact of the variant. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 2018

The c.3124_3125insAA pathogenic mutation, located in coding exon 29 of the MYBPC3 gene, results from an insertion of two nucleotides at position 3124, causing a translational frameshift with a predicted alternate stop codon (p.T1042Kfs*5). This mutation has been reported in multiple individuals with hypertrophic cardiomyopathy (Niimura H et al. N. Engl. J. Med., 1998 Apr;338:1248-57; Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61). 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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064793202; hg19: chr11-47355173;