rs397515935

chr11-47341137-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.1897+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. 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: 33)
• Consequence: MYBPC3 NM_000256.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.53

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, Cryptic splice site detected, with MaxEntScore 5.8, offset of 16, new splice context is: aggGTaggg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it 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 11-47341137-C-T is Pathogenic according to our data. Variant chr11-47341137-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 42582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47341137-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1897+1G>A		splice_donor_variant		ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1897+1G>A		splice_donor_variant		5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1897+1G>A		splice_donor_variant		5		A2
MYBPC3	ENST00000544791.1	c.1897+1G>A		splice_donor_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2021	Identified in multiple individuals with HCM referred for genetic testing at GeneDx and in published literature (Alfares et al., 2015; Walsh et al., 2017); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID#42582; Landrum et al., 2016); Not observed in large population cohorts (Lek 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; This variant is associated with the following publications: (PMID: 25611685, 27532257, 33673806) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Apr 14, 2016	- -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2017	The c.1897+1G>A variant in MYBPC3 has been identified by our laboratory in 3 ind ividuals with HCM and segregated with disease in 1 affected relative. It was abs ent from large population studies. This variant has been reported in ClinVar (Va riation ID:42582). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Splice site and other MYBPC3 variants resulting i n a heterozygous loss of function are strongly associated with HCM. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosom al dominant manner based upon its predicted loss of function impact, identificat ion in affected individuals, segregation with disease, and absence from controls . ACMG/AMP Criteria applied: PVS1; PM2; PS4_Supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 18, 2023	This sequence change affects a donor splice site in intron 19 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 individuals with hypertrophic cardiomyopathy (PMID: 25611685, 27532257). ClinVar contains an entry for this variant (Variation ID: 42582). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		4.9

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		0.93		Position offset: -15
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: rs397515935; hg19: chr11-47362688;