rs113358486

Variant names:

• chr11-47333555-A-C
• rs113358486
• NM_000256.3:c.3190+2T>G

Your query was ambiguous. Multiple possible variants found:

• chr11-47333555-A-C
• chr11-47333555-A-G
• chr11-47333555-A-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.3190+2T>G variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000207 in 1,447,602 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 5.80
• Publications: 6 publications found

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]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 11-47333555-A-C is Pathogenic according to our data. Variant chr11-47333555-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 42691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.3190+2T>G		splice_donor_variant, intron_variant	Intron 29 of 34	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3190+2T>G		splice_donor_variant, intron_variant	Intron 29 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3190+2T>G		splice_donor_variant, intron_variant	Intron 28 of 33	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000837 AC: 2 AN: 239022 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447602 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 720550

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111734

Other (OTH) AF: 0.00 AC: 0 AN: 60282

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000937 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27532257, 23690394, 26914223, 24111713, 29121657, 33673806) -

Hypertrophic cardiomyopathy Pathogenic:2

Jun 04, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3190+2T>G variant in MYBPC3 has been reported in at least 15 individuals w ith HCM and segregated with disease in 3 affected relatives from 2 families (Ber ge 2014, Walsh 2016, LMM data). It has also been identified in 2/111408 of Europ ean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org; dbSNP rs113358486). This variant occurs in the invariant region (+ /- 1,2) of the splice consensus sequence and is predicted to cause altered splic ing leading to an abnormal or absent protein. Heterozygous loss of function of t he MYBPC3 gene is an established disease mechanism in HCM. In summary, this vari ant meets criteria to be classified as pathogenic for HCM in an autosomal domina nt manner based upon predicted splicing impact, case observations, and segregati on studies. ACMG/AMP criteria applied: PVS1, PS4, PM2, PP1. -

Mar 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 29 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 present in population databases (rs113358486, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24111713, 26914223, 27532257). ClinVar contains an entry for this variant (Variation ID: 42691). 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. -

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

Apr 09, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Pathogenic:1

Jan 05, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a T to G nucleotide substitution at the +2 position of intron 29 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 26914223, 27532257, 28971120). This variant has been identified in 2/239022 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Dec 02, 2020

Clinical Genetics Laboratory, Region Ostergotland

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4, PP3, PP5, BP2 -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Nov 06, 2015

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Feb 25, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3190+2T>G intronic pathogenic mutation results from a T to G substitution two nucleotides after coding exon 29 in the MYBPC3 gene. This alteration has been detected in multiple individuals from cohorts reported to have hypertrophic cardiomyopathy (HCM) and in individuals referred for HCM genetic testing (Berge KE et al. Clin Genet. 2014;86(4):355-60; Walsh R et al. Genet Med. 2017 02;19(2):192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native 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	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Uncertain	0.98
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.8
GERP RS		4.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 2

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

Other links and lift over

dbSNP: rs113358486; hg19: chr11-47355106;