rs397516052

Positions:

• chr11-47350059-TG-T

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.459del​(p.Ile154LeufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,411,996 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: 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 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 11-47350059-TG-T is Pathogenic according to our data. Variant chr11-47350059-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 42755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47350059-TG-T is described in Lovd as [Pathogenic]. Variant chr11-47350059-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.459del	p.Ile154LeufsTer5	frameshift_variant	4/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.459del	p.Ile154LeufsTer5	frameshift_variant	4/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.459del	p.Ile154LeufsTer5	frameshift_variant	4/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.459del	p.Ile154LeufsTer5	frameshift_variant, NMD_transcript_variant	4/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1411996 Hom.: 0 Cov.: 35 AF XY: 0.00000143 AC XY: 1 AN XY: 697766

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: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.21e-7

Gnomad4 OTH exome AF: 0.00

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	Apr 26, 2023	Expression studies in neonatal rat ventricular cardiomyocytes showed this variant caused significantly reduced levels of a truncated protein and failed to exhibit sarcomere incorporation when compared to wild-type protein (Glazier et al., 2018); 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 23396983, 21959974, 28640247, 25335496, 29875314) -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 22, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ile154LeufsX5 (c.459delC) in MYBPC3 Given the data reviewed below, we consider this variant to be likely disease causing. This variant has been seen in at least 2 presumably unrelated individuals with HCM.. This variant has been reported in one Indian male who was 44 years of age and who had a 24 mm septum (Bashyam et al 2011). In that cohort another patient with HCM had c.456delC as well as a missense variant in MYBPC3, p.Glu710Lys. The authors do not report whether these two variants are cis or trans or any segregation data on either variant. Note in this publication the variant is notated as c.456delC, while GeneDx and HGMD refer to it as c.459delC. Unfortunately Bashyam et al don't include protein nomenclature that might help clarify what they are seeing. I checked with GeneDx about the discrepancy and they noted that the deleted C occurs in a string of Cs. They name the variant assuming the first C is deleted while Bashyam et al seem to notate assuming the last C is deleted (ACCC[C]ATTG vs. A[C]CCCATTTG). Zimmerman et al (2010) list this variant in a supplemental table of pathogenic variants for which genotyping probes were added to their resequencing array for dilated cardiomyopathy. This is a methods paper published by the Laboratory for Molecular Medicine team at Harvard. This suggests that they had reason to suspect this variant was pathogenic (likely unpublished internal data from their clinical genetic testing experience). This is a frame-shifting variant that creates a premature stop codon 5 codons downstream of the variant. The variant is expected to either cause a truncated protein or a completely absent protein due to nonsense-mediated mRNA decay. Many other frameshift and null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy; there are no frameshift variants listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6000 Caucasian and African American individuals (as of 7/30/2012). In total the variant has not been seen in 6100 published controls and publicly available general population samples, though note that all (or nearly all) of these samples do not match the patient’s ancestry. Bashyam et al report that the variant was absent in 100 presumably healthy controls (ancestry is not noted). GeneDx did not report control data. The variant is not listed in dbSNP or 1000 genomes. Nor is it not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6,000 Caucasian and African American individuals (as of July 2012). -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 03, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Ile154Leufs*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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 21959974, 23396983, 25335496). ClinVar contains an entry for this variant (Variation ID: 42755). For these reasons, this variant has been classified as Pathogenic. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397516052; hg19: chr11-47371610;