rs397515895

Positions:

• chr11-47343099-G-A

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.1273C>T​(p.Gln425Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q425Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.67

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 11-47343099-G-A is Pathogenic according to our data. Variant chr11-47343099-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 42517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47343099-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1273C>T	p.Gln425Ter	stop_gained	15/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1273C>T	p.Gln425Ter	stop_gained	15/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.1273C>T	p.Gln425Ter	stop_gained	14/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.1273C>T	p.Gln425Ter	stop_gained, NMD_transcript_variant	15/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459894 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726058

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 30, 2012	The Gln425X variant in MYBPC3 has been reported in 2 sporadic cases of late-onse t HCM (1 Polish and 1 of unspecified ancestry; Niimura 2002, Radzinski 2008). Th is variant has not been identified in large and broad European American and Afri can American populations by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS) though it remains possible that this variant is common in othe r populations. This variant leads to a premature termination codon at position 4 25, which is predicted to lead to a truncated or absent protein. Heterozygous lo ss-of-function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant meets our criteria to be classified as pathogenic (http:/ /pcpgm.partners.org/LMM) based on low frequency and the severity of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 08, 2020	This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 11815426, 18803133, 27532257). ClinVar contains an entry for this variant (Variation ID: 42517). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln425*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.82
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs397515895; hg19: chr11-47364650;