rs397516074

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E258Q) has been classified as Uncertain significance.

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:31

Conservation

PhyloP100: 7.86

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.772G>A	p.Glu258Lys	missense_variant, splice_region_variant	6/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.772G>A	p.Glu258Lys	missense_variant, splice_region_variant	6/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.772G>A	p.Glu258Lys	missense_variant, splice_region_variant	6/34	5		A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.772G>A	p.Glu258Lys	missense_variant, splice_region_variant, NMD_transcript_variant	6/27	5

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

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:

AN:

241524

Hom.:

AF XY:

0.0000229

AC XY:

AN XY:

131194

show subpopulations

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:

AN:

1452256

Hom.:

Cov.:

AF XY:

0.0000277

AC XY:

AN XY:

722342

show subpopulations

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:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

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.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:31

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 4

Pathogenic:10

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	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Center of Genomic medicine, Geneva, University Hospital of Geneva	May 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 07, 2023	Criteria applied: PS3,PS4,PM5 -

not provided

Pathogenic:6

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	Mayo Clinic Laboratories, Mayo Clinic	Apr 06, 2021	PS3, PS4, PP1, PP3 -
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	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	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	MYBPC3: PP1:Strong, PM5, PS3:Moderate, PS4:Moderate, PM2:Supporting, BP4 -

Hypertrophic cardiomyopathy

Pathogenic:6

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 5â€™ 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	Invitae	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	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". -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Loeys Lab, Universiteit Antwerpen	Feb 26, 2021	- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Dec 20, 2016	- -
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. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Pathogenic:2

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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 05, 2022	- -

Cardiomyopathy

Pathogenic:2

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. -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 30, 2023	- -

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

CardioboostCm

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

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

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.7

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over