chr11-47348424-C-T

Variant names:

• chr11-47348424-C-T
• rs397516074
• NM_000256.3:c.772G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.772G>A​(p.Glu258Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000337 in 1,604,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E258E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:33 U:1
• Conservation: PhyloP100: 7.86

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 12 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 11-47348424-C-T is Pathogenic according to our data. Variant chr11-47348424-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47348424-C-T is described in Lovd as [Pathogenic]. Variant chr11-47348424-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.772G>A	p.Glu258Lys	missense_variant, splice_region_variant	Exon 6 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.772G>A	p.Glu258Lys	missense_variant, splice_region_variant	Exon 6 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.772G>A	p.Glu258Lys	missense_variant, splice_region_variant	Exon 6 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.772G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152162 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000483

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

GnomAD3 exomes AF: 0.0000166 AC: 4 AN: 241524 Hom.: 0 AF XY: 0.0000229 AC XY: 3 AN XY: 131194

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000337 AC: 49 AN: 1452256 Hom.: 0 Cov.: 30 AF XY: 0.0000277 AC XY: 20 AN XY: 722342

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

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: 0.0000416

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152162 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000956 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000331 AC: 4

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:33 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 4 Pathogenic:12

Jan 03, 2022

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Missense variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 25031304, PVS!_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000022, PM2_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042792). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2015

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions and recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant is reported in the literature as p.(Glu258Lys). However, functional studies showed exon 6 skipping resulting in p.(Val219Argfs*42), predicted to undergo nonsense-mediated decay (NMD) (PMIDs: 15114369, 25031304). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 & v3: 9 heterozygotes, 0 homozygotes). (SP) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been previously reported as heterozygous in individuals with hypertrophic cardiomyopathy, and as pathogenic by many clinical testing laboratories (VCGS, ClinVar, PMIDs: 25031304, 27532257). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 21, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The MYBPC3 Glu258Lys is a rare variant, with an allele frequency of 0.000039 in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). This variant has been reported in multiple unrelated HCM patients (see references), and is observed to be shared in up to ~14% of unrelated HCM cases in Italian cohorts, suggesting a founder effect (Girolami et al, 2006; Olivotto et al, 2008). Segregation analyses support its pathogenic role (Niimura et al., 1998; Girolami et al., 2006). In silico tools (SIFT, PolyPhen-2, MutationTaster) predict this variant to be disease causing. Furthermore, this variant affects the splice site consensus sequence (last base of exon 6) and has been shown to result in truncated MYBPC3 protein due to exon skipping (Anderson et al., 2004; Sarikas et al., 2005; Helms AS, et al., 2014). Functional studies have shown that the truncated protein is incorporated into cardiac sarcomeres and impairs contractile function (De Lange et al., 2013). We have identified MYBPC3 Glu258Lys in 3 HCM probands. In summary, based on rarity in the general population, observation in multiple unrelated HCM cases and because loss of function is a mechanism of disease for MYBPC3, we classify this variant as "pathogenic". -

Dec 07, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3,PS4,PM5 -

May 09, 2017

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 02, 2023

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYBPC3 c.772G>A (p.Glu258Lys) missense variant results in the substitution of glutamic acid at amino acid position 258 with lysine. Across a selection of the available literature, this variant has been identified in a heterozygous state in greater than 50 unrelated individuals with hypertrophic cardiomyopathy (PMID: 18533079; PMID: 27532257). The highest frequency of this allele in the Genome Aggregation Database is 0.00004410 in the European (non-Finnish) population (version 3.1.2). This variant's nucleotide position coincides with a canonical splice donor site. Functional experiments using patient tissues have demonstrated an effect on splicing that leads to skipping of exon 6, which results in nonsense-mediated mRNA decay due to a premature stop codon (PMID: 15114369; PMID: 19574547). In addition, transgenic rescue experiments performed in cultured murine cardiomyocytes have demonstrated reduced contractile force and altered contractile kinetics due to the presence of the p.Glu258Lys variant independent of any effects on splicing (PMID: 23980194). A knock-in mouse carrying this variant has been developed and displays the hallmark phenotype of hypertrophic cardiomyopathy (PMID: 19590044). Based on the available evidence, the c.772G>A (p.Glu258Lys) variant is classified as pathogenic for hypertrophic cardiomyopathy. -

Aug 01, 2017

Phosphorus, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 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.772G>A (p.Glu258Lys) variant in the MYBPC3 gene has been reported in multiple unrelated individuals with hypertrophic cardiomyopathies (PMID: 9562578, 12707239, 15114369, 15563892, 16858239, 18533079, 23233322, 25031304). This variant has an extremely low frequency in large databases of genetic variation in the general population. mRNA studies demonstrated that this variant resulted in skipping of exon 6 (PMID: 15114369, 25031304). Therefore, this c.772G>A (p.Glu258Lys) variant in the MYBPC3 gene is classified as pathogenic. -

Feb 26, 2020

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: PS3,Ps4-MOD,PM2,PP1-M,PP3. -

not provided Pathogenic:7

Oct 28, 2015

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYBPC3: PP1:Strong, PM5, PS3:Moderate, PS4:Moderate, PM2:Supporting, BP4 -

Apr 06, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PP1, PP3 -

Oct 28, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported to segregate with disease in multiple families (Niimura et al., 1998; Richard et al., 2003; Ho et al., 2009; Zhao et al., 2017); Proposed as an Italian founder mutation (Girolami et al., 2006; Olivotto et al., 2008); Observed in 6/272910 global alleles in large population cohorts (Lek et al., 2016); Located in the last nucleotide position of exon 6, which is part of the splice donor site; Functional studies have demonstrated that the E258K variant leads to aberrant gene splicing of exon 6 (Andersen et al., 2004; Vignier et al., 2009; Helms et al., 2014); Additional studies suggest this variant may result in rapid protein degradation (Sarikas et al., 2005; Vignier et al., 2009) or, if abnormal protein is expressed, it may lead to altered protein interaction and contractile kinetics (De Lange et al., 2013); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID 42792; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26671970, 30550750, 27532257, 23233322, 15114369, 29875424, 30165862, 28687478, 28679633, 30972196, 9562578, 19574547, 20359594, 18533079, 23283745, 22907696, 25031304, 23980194, 12951062, 26914223, 25971843, 21310275, 12707239, 15563892, 15519027, 23527136, 19590044, 15769446, 20031602, 22267749, 16858239, 28450932, 28790153, 29524613, 28916354, 12974739, 18957093, 27574918, 27267291, 27600940, 26869393, 25351510, 29447731, 30645170, 30446606, 31006259, 31737537, 31447099, 33673806, 33297573, 32686758) -

Jul 29, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Pathogenic:5 Uncertain:1

May 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu258Lys variant in MYBPC3 has been reported in multiple HCM probands and segregated in many additional affected family members (Girolami 2006, Marston 2009, Niimura 1998, Nanni 2003, Olivotto 2008, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42792) and has been identified in 4/124374 of European and in 2/23498 of African chromosomes by gnomAD (https://gnomad.broadinstitute.org/). The p.Glu258Lys variant is located in the last base of exon 6, which is part of the 5’ splice region. Functional studies using patient RNA have shown that this alteration affects splicing, leading to skipping of exon 6, which is predicted to result in a frameshift, premature termination and therefore likely in a loss of function (Andersen 2004, Martson 2009). Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM based on case observations, segregation with disease, low frequency in the general population and observed impact on splicing. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting, PS3_Moderate. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 258 of the MYBPC3 protein (p.Glu258Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs397516074, gnomAD 0.009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 9562578, 12707239, 15563892, 18533079, 20031602, 22267749, 23233322). This variant is also known as E264K. ClinVar contains an entry for this variant (Variation ID: 42792). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 15769446, 19590044, 23980194). Studies have shown that this missense change results in skipping of exon 6, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 15114369, 19574547, 25031304). For these reasons, this variant has been classified as Pathogenic. -

Feb 26, 2021

Loeys Lab, Universiteit Antwerpen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2023

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYBPC3 c.772G>A variant is classified as Pathogenic (PS3, PS4) MYBPC3 c.772G>A is a single nucleotide variant located at the last nucleotide of exon 6/35 of the MYBPC3 gene which is predicted to change the amino acid glutamic acid at position 258 in the protein to lysine. The variant has been reported in excess of 70 probands with a clinical presentation of hypertrophic cardiomyopathy (PS4) and is reported to segregate with disease in multiple families (PMID#9562578, 16858239). Well-established functional studies show this variant impacts splicing, resulting in a deletion of exon 6 and downstream truncation of the MYBPC3 protein (PMID#3980194, 25031304, 28679633, 30645170, 34097875, 19590044) (PS3). This variant has been reported in dbSNP (rs397516074), reported as disease causing in the HGMD database (CM981322) and is reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 42792). -

-

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 09, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant alters the conserved c.G nucleotide at the last nucleotide position of exon 6 in the MyBP-C motif of the MYBPC3 gene. RNA studies using blood and myocardial samples from carriers have shown that this variant causes out-of-frame skipping of exon 6, resulting in premature truncation (PMID: 15114369, 19574547, 25031304, 30645170). A study using engineered mouse cardiac tissue has shown that this variant disrupts the interaction between MYBPC3 and myosin protein and accelerates contractile kinetics (PMID: 23980194). In a knock-in mouse model, this variant causes left ventricular hypertrophy and reduced fractional shortening, consistent with hypertrophic cardiomyopathy phenotype (PMID: 19590044). This variant has been reported in over 50 individuals affected with hypertrophic cardiomyopathy from various populations (PMID: 12707239, 12951062, 12974739, 14563344, 15563892, 16858239, 18533079, 19808356, 19574547, 23233322, 30645170, 34680864, 37498360, Marschall et al., 2019) and is particularly common in the Italian population (PMID: 16858239, 18533079). This variant has been shown to segregate with disease in a family study (PMID: 9562578). This variant has been identified in 6/272910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Primary familial hypertrophic cardiomyopathy Pathogenic:3

Dec 20, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 12, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MYBPC3 c.772G>A (p.Glu258Lys) variant involves the alteration of a conserved nucleotide located just one nucleotide upstream from an exon-intron junction. 3/5 in silico tools predict a damaging outcome for this variant. 5/5 programs via Alamut predict that this variant affects normal splicing. Multiple functional studies confirmed that the variant leads to exon 6 skipping resulting in a premature stop codon (Anderson_2004, Helms_2014). Heterozygous loss-of-function due to mutations in the MYBPC3 gene is an established disease mechanism in HCM. This variant was found in 5/270526 control chromosomes at a frequency of 0.0000185, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). The variant has been recurrently found in numerous patients with HCM and is reported to cosegregate with the disease (Niimura_1998; Girolami_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Sep 07, 2015

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:2

Sep 21, 2022

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.772G>A variant in MYBPC3 has previously been reported in individuals with noncompaction cardiomyopathy [PMID:29447731], hypertrophic cardiomyopathy [PMID:15114369,25031304, 22267749, 23233322, 30645170, 30972196], and was found to segregate in many additional affected family members [PMID:9562578]. This variant has been deposited in ClinVar [ClinVar ID: 42792] as Pathogenic/Likely Pathogenic. The c.772G>A variant is observed in 17 alleles (0.0021% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.772G>A variant in MYBPC3 is located in exon 6 of this 35-exon gene and is predicted to replace a moderately conserved glutamic acid with lysine amino acid at position 285 p.(Arg123Gln) in the phosphorylation domain of the c1 motif of the encoded protein [PMID:28658286,23233322, 15114369]. In addition, the c.772G>A variant is located one nucleotide away from the exon-intron junction of exon 6, therefore it may also affect the splicing. In vitro functional RNA studies using blood and myocardial samples have shown to cause out-of-frame skipping of exon 6, resulting in premature truncation cells carrying c.772G>A variant [PMID: 15114369, 25031304, 30645170]. Besides, this variant has demonstrated to alter protein interactions, contractile kinetics and caused left ventricular hypertrophy, reduced fractional shortening consistent with hypertrophic cardiomyopathy phenotype in mouse models [PMID: 19590044]. In silico predictions are inconclusive for p.(Arg123Gln) variant's effect [(CADD v1.6 = 51, REVEL = 0.616)]. Based on available evidence, this c.772G>A p.(Glu258Lys) variant identified in MYBPC3 is classified as Pathogenic. -

Jan 05, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Pathogenic:2

Apr 06, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant alters the conserved c.G nucleotide at the last nucleotide position of exon 6 of the MYBPC3 gene. RNA studies using blood and myocardial samples from carriers have shown that this variant causes out-of-frame skipping of exon 6, resulting in premature truncation (PMID: 15114369, 19574547, 25031304, 30645170). A study using engineered mouse cardiac tissue has shown that this variant disrupts the interaction between MYBPC3 and myosin protein and accelerates contractile kinetics (PMID: 23980194). In a knock-in mouse model, this variant causes left ventricular hypertrophy and reduced fractional shortening, consistent with hypertrophic cardiomyopathy phenotype (PMID: 19590044). This variant has been reported in over 50 individuals affected with hypertrophic cardiomyopathy from various populations (PMID: 12707239, 12951062, 14563344, 12974739, 15114369, 15563892, 16858239, 1853307, 19808356, 19574547, 22267749, 23233322, 30645170, Marschall et al., 2019) and is particularly common in the Italian population (PMID: 16858239, 18533079). This variant has been shown to segregate with disease in a family study (PMID: 9562578). This variant has been identified in 6/272910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

May 30, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Left ventricular noncompaction 10 Pathogenic:1

Nov 02, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Mar 30, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.772G>A pathogenic mutation (also known as p.E258K), located in coding exon 6 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 772. The glutamic acid at codon 258 is replaced by lysine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. In one study, RT-qPCR analysis showed that the altered allele resulted in skipping of exon 6 and all of the mutant transcripts were truncated (Helms AS et al. Circ Cardiovasc Genet. 2014;7(4):434-43). This alteration has been identified in multiple individuals with hypertrophic cardiomyopathy (HCM) with co-segregation and a suggested founder effect (Niimura H et al. N Engl J Med. 1998;338(18):1248-57; Girolami F et al. J Cardiovasc Med (Hagerstown). 2006;7(8):601-7; Bongini C. Am J Cardiol. 2016;117(7):1151-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
CardioboostCm	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.7	M;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.62
Sift	Benign	0.047	D;D;D
Sift4G	Benign	0.069	T;T;T
Polyphen		0.79	P;.;.
Vest4		0.95
MutPred		0.85		Gain of ubiquitination at E258 (P = 0.0121);Gain of ubiquitination at E258 (P = 0.0121);Gain of ubiquitination at E258 (P = 0.0121);
MVP		0.90
MPC		0.79
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.46
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516074; hg19: chr11-47369975; COSMIC: COSV99920527;