11-47346206-C-T

Position:

• chr11-47346206-C-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.1090+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,506 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.50

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: Splicing +-2 bp (donor or acceptor) 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
• PP5: Variant 11-47346206-C-T is Pathogenic according to our data. Variant chr11-47346206-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 177668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47346206-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-47346206-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1090+1G>A		splice_donor_variant		ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1090+1G>A		splice_donor_variant		5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.1090+1G>A		splice_donor_variant		5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.1090+1G>A		splice_donor_variant, NMD_transcript_variant		5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461506 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727030

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2017	The c.1090+1 G>A variant has been reported previously in one individual with HCM from a cohort of 88 Italian patients, and was absent from 200 control chromosomes (Girolami et al., 2006). The c.1090+1 G>A variant is predicted to destroy the canonical splice donor site in intron 12 and to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site variants in the MYBPC3 gene associated with HCM have been reported in HGMD, including two other nucleotide changes at the same position (c.1090+1G>T/C) (Stenson et al., 2014). Furthermore, the c.1090+1 G>A variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.1090+1 G>A in the MYBPC3 gene is interpreted as a pathogenic variant. -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.1090+1G nucleotide in the MYBPC3 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 22112859, 22989827, 26914223). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 177668). This variant is also known as IVS12+1G>A. Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 16858239, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 12 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). -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 04, 2013	proposed classification - variant undergoing re-assessment, contact laboratory -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is not observed in the gnomAD v2.1.1 dataset. Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000177668). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2019

The c.1090+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 12 of the MYBPC3 gene. This variant (also known as IVS12+1G>A) has been reported in multiple hypertrophic cardiomyopathy (HCM) cohorts and HCM testing cohorts, although clinical details were limited in some cases (Girolami F et al. J Cardiovasc Med (Hagerstown), 2006 Aug;7:601-7; Olivotto I et al. Mayo Clin. Proc., 2008 Jun;83:630-8; Lopes LR et al. J. Med. Genet., 2013 Apr;50:228-39; Walsh R et al. Genet. Med., 2017 02;19:192-203). Additional variants impacting this donor splice site, c.1090+1G>T and c.1090+1G>C, have also been reported in individuals with HCM (Walsh R et al. Genet. Med., 2017 02;19:192-203; Millat G et al. Clin. Chim. Acta, 2010 Dec;411:1983-91). 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	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
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: rs727504269; hg19: chr11-47367757;