chr11-47339718-AG-C

Position:

• chr11-47339718-AG-C

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PS1 PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.1999_2000delCTinsG​(p.Leu667fs) variant causes a frameshift, missense 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 frameshift, missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.73

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 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS1: Transcript NM_000256.3 (MYBPC3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47339718-AG-C is Pathogenic according to our data. Variant chr11-47339718-AG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164091.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.1999_2000delCTinsG	p.Leu667fs	frameshift_variant, missense_variant	21/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1999_2000delCTinsG	p.Leu667fs	frameshift_variant, missense_variant	21/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1999_2000delCTinsG	p.Leu667fs	frameshift_variant, missense_variant	20/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1999_2000delCTinsG		non_coding_transcript_exon_variant	21/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2023	For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with hypertrophic or dilated cardiomyopathy (PMID: 20474083, 24793961, 27532257). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change creates a premature translational stop signal (p.Leu667Aspfs*15) 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	All of Us Research Program, National Institutes of Health	Jul 23, 2024	This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. This prediction has not been confirmed by functional studies. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 7532257, 25611685, 20474083, 28840316, 30297972, 32841044) .This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 08, 2013	The Leu667fs variant in MYBPC3 has been identified by our laboratory in 2 Hispan ic individuals with HCM. Data from large population studies is insufficient to a ssess the frequency of this variant. This frameshift variant is predicted to alt er the protein?s amino acid sequence beginning at position 667 and lead to a pre mature termination codon 15 amino acids downstream. This alteration is then pred icted to lead to a truncated or absent protein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, this variant meets our criteria to be classified as pathogenic (http:/ /pcpgm.partners.org/LMM) based on the predicated impact of the variant. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 06, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jan 25, 2022	The c.1999_2000delCTinsG (p.Leu667AspfsTer15) variant identified in the MYBPC3 gene resulting in a frameshift at amino acid 667/1275 (exon 21/35) is predicted to lead to the premature termination of the protein 15 amino acids downstream and is expected to result in either an abnormal, truncated protein product or loss of protein through nonsense-mediated mRNA decay. The variant has been reported in several individuals affected with hypertrophic cardiomyopathy in the literature (PMID: 20474083, 24793961, 27532257). The variant has 0.0001117 allele frequency in the gnomAD (v3.1.2) database (17 out of 152182 heterozygous alleles, no homozygotes). The variant is reported as Pathogenic by multiple submitters in ClinVar (Variation ID: 164091). Based on the available evidence, the heterozygous c.1999_2000delCTinsG (p.Leu667AspfsTer15) variant identified in the MYBPC3 gene is reported as Likely Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 12, 2022

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; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 164091; ClinVar); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20474083, 24793961, 27532257, 27535533) -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Division of Medical Genetics, University of Washington

May 05, 2020

This variant leads to a translational frameshift and the introduction of a premature termination codon 15 residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of MYBPC3 is a well-established mechanism of disease for hypertrophic cardiomyopathy (Marston 2009). This variant has been reported in the literature in multiple individuals with hypertrophic or dilated cardiomyopathy (Zimmerman 2010, Bos 2014, Walsh 2017). This variant has an overall allele frequency of 0.00004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. PVS1 -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

The c.1999_2000delCTinsG pathogenic mutation, located in coding exon 21 of the MYBPC3 gene, results from the deletion of two nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.L667Dfs*15). This alteration has been reported in subjects with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) (Zimmerman RS et al. Genet. Med., 2010 May;12:268-78; Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Walsh R et al. Genet. Med., 2017 02;19:192-203). 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: rs727503192; hg19: chr11-47361269;