11-47332813-C-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_000256.3(MYBPC3):c.3490+1G>A variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.76

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: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-47332813-C-T is Pathogenic according to our data. Variant chr11-47332813-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 42715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47332813-C-T is described in Lovd as [Pathogenic]. Variant chr11-47332813-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.3490+1G>A		splice_donor_variant		ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3490+1G>A		splice_donor_variant		5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.3490+1G>A		splice_donor_variant		5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 03, 2023	This sequence change affects a donor splice site in intron 31 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 9218526, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42715). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 10, 2012	The 3490+1 G>A variant in MYBPC3 has been identified an individual with HCM, seg regated with disease in 4 affected relatives and was absent from 3 unaffected re latives as well as 500 control chromosomes (Rottbauer 1997). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and results in exon skipping, leading to a frameshift and premature termination codon (Rottb auer 1997), which is predicted to lead to an abnormal or absent protein. Loss of function of the MYBPC3 gene is an established mechanism of disease for HCM. In summary, this variant meets our criteria to be classified as pathogenic (http:// pcpgm.partners.org/LMM) based upon the severe impact of the protein. -
Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Dec 13, 2017	MYBPC3 c.3490+1G>A has been previously reported in at least 4 HCM cases (Walsh R, et al., 2017; Weissler-Snir A, et al., 2017; Ehlermann P, et al., 2008; Rottbauer W, et al., 1997) and was found to segregate to multiple affected individuals in 2 families (Ehlermann P, et al., 2008; Rottbauer W, et al., 1997). We identified this variant in 2 HCM probands (1 North-West European descent, 1 Aboriginal), both of whom have no family history of disease. The variant is absent in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), as well as the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tool MaxEntScan predicts that the variant will affect splicing. In summary, based on multiple reports in HCM cases, strong segregation in affected individuals, rarity of the variant in the general population and because MYBPC3 loss of function variants are an established cause of HCM, we classify MYBPC3 c.3490+1G>A as 'Pathogenic'. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 01, 2020

Published functional studies demonstrate abnormal gene splicing with exon skipping (Rottbauer et al., 1997); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 42715; Landrum et al., 2016); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28790153, 28193612, 27532257, 9218526) -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 15, 1997

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2023

The c.3490+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 31 of the MYBPC3 gene. This variant has been detected in unrelated individuals with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with HCM in families (Rottbauer W et al. J Clin Invest, 1997 Jul;100:475-82; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10; Weissler-Snir A et al. Circ Cardiovasc Imaging, 2017 Feb;10; Walsh R et al. Genet Med, 2017 Feb;19:192-203;Chung H et al. J Cardiovasc Magn Reson, 2021 Mar;23:18; Burstein DS et al. Pediatr Res, 2021 May;89:1470-1476). RNA studies performed on samples from carriers of this variant have indicated that this variant results in exon skipping (Rottbauer W et al. J Clin Invest, 1997 Jul;100:475-82). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.71		Position offset: -4
DS_DL_spliceai		1.0		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516020; hg19: chr11-47354364;