rs397516074
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong
The NM_000256.3(MYBPC3):โc.772G>Aโ(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 (โ โ ). Synonymous variant affecting the same amino acid position (i.e. E258E) has been classified as Likely benign.
Frequency
Genomes: ๐ 0.000033 ( 0 hom., cov: 30)
Exomes ๐: 0.000034 ( 0 hom. )
Consequence
MYBPC3
NM_000256.3 missense, splice_region
NM_000256.3 missense, splice_region
Scores
5
8
7
Splicing: ADA: 1.000
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYBPC3 | NM_000256.3 | c.772G>A | p.Glu258Lys | missense_variant, splice_region_variant | 6/35 | ENST00000545968.6 | NP_000247.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.772G>A | p.Glu258Lys | missense_variant, splice_region_variant | 6/35 | 5 | NM_000256.3 | ENSP00000442795 | P4 | |
| MYBPC3 | ENST00000399249.6 | c.772G>A | p.Glu258Lys | missense_variant, splice_region_variant | 6/34 | 5 | ENSP00000382193 | A2 | ||
| MYBPC3 | ENST00000544791.1 | c.772G>A | p.Glu258Lys | missense_variant, splice_region_variant, NMD_transcript_variant | 6/27 | 5 | ENSP00000444259 |
Frequencies
GnomAD3 genomes 0.0000329 AC: 5AN: 152162Hom.: 0 Cov.: 30
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:33Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy 4 Pathogenic:11
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 02, 2022 | 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 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 07, 2023 | Criteria applied: PS3,PS4,PM5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 02, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Oct 02, 2018 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | May 09, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Feb 26, 2020 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,Ps4-MOD,PM2,PP1-M,PP3. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Phosphorus, Inc. | Aug 01, 2017 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Genetics and Molecular Cardiology, University of Sรฃo Paulo | - | - - |
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 28, 2019 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 03, 2015 | - - |
| Pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Oct 28, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jul 29, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | MYBPC3: PP1:Strong, PM5, PS3:Moderate, PS4:Moderate, PM2:Supporting, BP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 06, 2021 | PS3, PS4, PP1, PP3 - |
Hypertrophic cardiomyopathy Pathogenic:6Uncertain:1
| Uncertain significance, no assertion criteria provided | research | Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Loeys Lab, Universiteit Antwerpen | Feb 26, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 09, 2024 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | 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 disrupted 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 introduces a premature termination codon (PMID: 15114369, 19574547, 25031304). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 14, 2019 | 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 5รขโฌโข 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jun 14, 2023 | 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). - |
| Pathogenic, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Mar 21, 2017 | 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". - |
Primary familial hypertrophic cardiomyopathy Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Sep 07, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 12, 2017 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Dec 20, 2016 | - - |
Cardiomyopathy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 30, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 06, 2023 | 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. - |
Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 05, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Sep 21, 2022 | 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. - |
Left ventricular noncompaction 10 Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Nov 02, 2021 | - - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 30, 2022 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Benign
D;D;D
Sift4G
Benign
T;T;T
Polyphen
P;.;.
Vest4
MutPred
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
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at