rs376395543

Variant names:

• chr11-47351507-T-C
• rs376395543
• NM_000256.3:c.26-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.26-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000392 in 1,581,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:33
• Conservation: PhyloP100: 5.77
• Publications: 12 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 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06980392 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.9, offset of 6, new splice context is: acctggcccttcggtctcAGctt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 11-47351507-T-C is Pathogenic according to our data. Variant chr11-47351507-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 42644.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.26-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 34	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.26-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.26-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 33	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.26-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 26	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000268 AC: 6 AN: 223986 AF XY: 0.0000409

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000306

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000498

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000413 AC: 59 AN: 1428814 Hom.: 0 Cov.: 36 AF XY: 0.0000454 AC XY: 32 AN XY: 705224

African (AFR) AF: 0.0000304 AC: 1 AN: 32948

American (AMR) AF: 0.0000463 AC: 2 AN: 43166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24830

East Asian (EAS) AF: 0.00 AC: 0 AN: 38974

South Asian (SAS) AF: 0.00 AC: 0 AN: 83180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 0.0000504 AC: 55 AN: 1090474

Other (OTH) AF: 0.0000170 AC: 1 AN: 58888

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000215 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000332 AC: 4

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:33

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:11

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 26, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 27532257, 25637381, 18957093, 24510615, 29029073, 15519027, 22267749, 21750094, 27831900, 23674513, 34542152, 35537032, 33258288, 34570182, 32686758, 34691145, 31447099, 33673806, 33087929, 34135346, 37652022, 34493867, 36264615, 37767697, 39160446, 34714385)

Apr 06, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYBPC3 c.26-2A>G variant (rs376395543) is reported in the literature in multiple individuals affected with hypertrophic cardiomyopathy or left ventricular noncompaction and segregates with disease in several kindreds (Ehlermann 2008, Hathaway 2021, McGurk 2023, Sedaghat-Hamedani 2017, Van Driest 2004, Walsh 2017). This variant has been reported to be incompletely penetrant (McGurk 2023, Sedaghat-Hamedani 2017), and it is found in the general population with an overall allele frequency of 0.003% (7/255,378 alleles) in the Genome Aggregation Database (v2.1.1). This variant disrupts the canonical splice acceptor site of intron 1, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Ehlermann P et al. Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene. BMC Med Genet. 2008 Oct 28;9:95. PMID: 18957093. Hathaway J et al. Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients. BMC Cardiovasc Disord. 2021 Mar 5;21(1):126. PMID: 33673806. McGurk KA et al. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. Am J Hum Genet. 2023 Sep 7;110(9):1482-1495. PMID: 37652022. Sedaghat-Hamedani F et al. Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy. Eur Heart J. 2017 Dec 7;38(46):3449-3460. PMID: 29029073. Van Driest SL et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004 Nov 2;44(9):1903-10. PMID: 15519027. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257.

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYBPC3: PVS1, PM2

Jan 27, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 04, 2022

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_STR, PS4, PVS1_MOD, PM2_SUP

Hypertrophic cardiomyopathy 4 Pathogenic:5

May 29, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 08, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PP3.

Jun 29, 2021

Clinical Genomics Laboratory, Stanford Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.26-2A>G variant in the MYBPC3gene has been previously reported in many unrelated individuals with hypertrophic cardiomyopathy(Van Driest et al., 2004; Ehlermann et al., 2008; Kapplinger et al., 2014; Walsh et al., 2017), and segregated in 6 affected relatives from a five-generation family with left ventricular non-compaction (Sedaghat-Hamedani et al., 2017). This variant has been identified in6/115,748 European non-Finnish chromosomes(7/255,378 chromosomesoverall)by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with the prevalence of hypertrophic cardiomyopathy.The c.26-2A>G variant alters the canonical acceptor splice site in intron 1, which is predicted to result in abnormal gene splicing.Heterozygous loss-of-function is an established mechanism of disease for the MYBPC3gene(Helms et al., 2020).These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.26-2A>G variant as pathogenic for autosomal dominant hypertrophic cardiomyopathy based on the information above. [ACMG evidence codes used: PVS1_Strong; PS4; PM2; PP1]

Nov 07, 2022

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypertrophic cardiomyopathy Pathogenic:5

Sep 18, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an A to G nucleotide substitution at the -2 position of intron 1 splice acceptor site of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although RNA studies have not been reported, this variant is expected to disrupt RNA splicing and result in an absent or non-functional protein product. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 18957093, 21750094, 22267749, 23674513, 24510615, 27532257, 27831900) and has been shown to segregate with disease in 4 individuals from 2 families (communication with en external laboratory; ClinVar SCV000059162.6). This variant has been identified in 7/255378 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.

Aug 29, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.26-2A>G variant in MYBPC3 has been reported in >10 individuals with HCM, segregated with disease in 4 affected relatives from 3 families, including 1 obligate carrier (Van Driest 2004, Ehlermann 2008, Waldmuller 2011, Page 2012, Kapplinger 2014, LMM unpublished data). It has also been reported in ClinVar (Variation ID 42644), in 7/114350 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs376395543), and in 2 unaffected adults (Natarajan 2016, LMM unpublished data). For diseases with clinical variability and reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Finally, this variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence, and the variant is predicted to damage the canonical splice site. Heterozygous splice variants in MYBPC3 are prevalent in cases of HCM. However, an alternate splice site is predicted to occur 6 bps downstream, and, if used, would lead to an in-frame deletion of 2 amino acids, though these computational tools are not predictive enough to suggest this alternative splice site would be use in vivo. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon predicted impact to the protein, presence in affected individuals and segregation studies. The ACMG/AMP Criteria applied: PS4; PM4; PP1_Supporting; PM2_Supporting.

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 1 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 (rs376395543, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15519027, 18957093, 22267749, 23674513, 24510615, 27532257). ClinVar contains an entry for this variant (Variation ID: 42644). 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.

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Jul 18, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.26-2A>G variant of the MYBPC3 gene disrupts the splicing acceptor site in intron 1 and is expected to alter RNA splicing, leading to disrupted protein structure and function. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 18957093, 21750094, 22267749, 23674513, 24510615, 27532257, 27831900). This variant has been identified in 3/255378 chromosomes in the general population by the gnomAD database. Based on these evidence, the c.26-2A>G variant of the MYBPC3 gene is classified as pathogenic.

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:3

Mar 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYBPC3 NM_000256.3 exon 2 c.26-2A>G: This variant has been reported in the literature in several individuals with HCM or LVNC, segregating with disease in multiple affected family members within at least two families (Van Driest 2004 PMID:15519027, Ehlermann 2008 PMID:18957093, Page 2012 PMID:22267749, Sedaghat-Hamedani 2017 PMID:29029073, Walsh 2017 PMID:27532257). This variant is present in 0.005% (6/115748) of European alleles in the Genome Aggregation Database http://gnomad.broadinstitute.org/variant/11-47373058-T-C). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, reduced penetrance, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:42644). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Marston 2009 PMID:19574547). In summary, this variant is classified as pathogenic based on the data above (segregation studies, impact to protein etc.)

Sep 16, 2022

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.26-2A>G variant identified in the MYBPC3 gene has been reported in ClinVar as Pathogenic by multiple submitters (VarID:42644) and has been reported in several individuals affected with hypertrophic cardiomyopathy in the literature [PMID: 15519027, 18957093, 27532257, 33673806,others.] The c.26-2A>G variant is observed in 10 alleles (~0.002% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2,TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.26-2A>G variant in MYBPC3 is located inthe canonical splice acceptor site preceding exon 2 of this 34-exon gene, and is presumed to affect mRNA splicing which might result in exon skipping or full/partial intron retention. Based on available evidence this c.26-2A>G variant identified in MYBPC3 is classified as Pathogenic.

Left ventricular noncompaction 10 Pathogenic:2

Jan 27, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 26, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2

Cardiomyopathy Pathogenic:2

Sep 08, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 08, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an A to G nucleotide substitution at the -2 position of intron 1 splice acceptor site of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although RNA studies have not been reported, this variant is expected to disrupt RNA splicing and result in an absent or non-functional protein product. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 18957093, 21750094, 22267749, 23674513, 24510615, 27532257, 27831900) and has been shown to segregate with disease in 4 individuals from 2 families (communication with en external laboratory; ClinVar SCV000059162.6). This variant has also been identified in 20 individuals from a large population study who were not known to be affected with hypertrophic cardiomyopathy (PMID: 37652022). This variant has been identified in 7/255378 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.

MYBPC3-related disorder Pathogenic:2

Mar 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.26-2A>G variant is located in a canonical splice-site, and it is not predicted the protein reading frame alteration, however, occur in a critical region and the variant disrupts <10% of protein - PVS1_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 42644; PMID: 15519027; PMID: 18957093; PMID: 23674513; PMID: 24510615; PMID: 22267749; PMID: 27532257) - PS4. The variant is present at low allele frequencies population databases (rs376395543 – gnomAD 0.0002741%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 18957093; 22267749) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic.

Aug 14, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYBPC3 c.26-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in multiple patients with hypertrophic cardiomyopathy (Ehlermann et al. 2008. PubMed ID: 18957093; Witjas-Paalberends et al. 2013. PubMed ID: 23674513; Kapplinger et al. 2014. PubMed ID: 24510615). This variant is reported in 0.0052% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47373058-T-C). Variants that disrupt the consensus splice acceptor site in MYBPC3 are expected to be pathogenic. This variant is interpreted as pathogenic.

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Intellectual disability Pathogenic:1

Aug 03, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant c.26-2A>G, p.? was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was unknown.The variants does not (fully) explain the NDD in this individual

Cardiovascular phenotype Pathogenic:1

Sep 20, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.26-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 2 in the MYBPC3 gene. This mutation has been previously reported in individuals with hypertrophic cardiomyopathy (HCM) and left ventricular non-compaction (LVNC) (Page SP et al. Circ Cardiovasc Genet. 2012;5(2):156-66; Ehlermann P et al. BMC Med Genet. 2008;9:95; Van Driest SL et al. J Am Coll Cardiol. 2004;44(9):1903-10; Sedaghat-Hamedani F et al. Eur. Heart J., 2017 Dec;38:3449-3460; Walsh R et al. Genet. Med., 2017 02;19:192-203). 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	Benign	-0.0012	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	35
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0	.;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.0	.;.;.
MetaRNN	Benign	0.0	.;.;.
MutationAssessor	Benign	0.0	.;.;.
PhyloP100		5.8
PROVEAN	Benign	0.0	.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.
Sift4G	Pathogenic	0.0	.;.;.
Vest4		0.0
GERP RS		4.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.89		Position offset: -8
DS_AL_spliceai		0.95		Position offset: -2

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

Other links and lift over

dbSNP: rs376395543; hg19: chr11-47373058;