rs375882485

chr11-47342698-G-Achr11-47342698-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_000256.3(MYBPC3):c.1504C>T(p.Arg502Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000144 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R502G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:29 O:2
• Conservation: PhyloP100: 4.49

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 14 ACMG points.

• PM1: In a domain Ig-like C2-type 3 (size 90) in uniprot entity MYPC3_HUMAN there are 51 pathogenic changes around while only 13 benign (80%) in NM_000256.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47342697-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• PP5: Variant 11-47342698-G-A is Pathogenic according to our data. Variant chr11-47342698-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47342698-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-47342698-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1504C>T	p.Arg502Trp	missense_variant	17/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1504C>T	p.Arg502Trp	missense_variant	17/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1504C>T	p.Arg502Trp	missense_variant	16/34	5		A2
MYBPC3	ENST00000544791.1	c.1504C>T	p.Arg502Trp	missense_variant, NMD_transcript_variant	17/27	5

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000401 AC: 10 AN: 249240 Hom.: 0 AF XY: 0.0000444 AC XY: 6 AN XY: 135212

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000151 AC: 220 AN: 1461698 Hom.: 0 Cov.: 31 AF XY: 0.000138 AC XY: 100 AN XY: 727134

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000188

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74358

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000478 Hom.: 0

Bravo AF: 0.0000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:29 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:10

Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 08, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Arg502Trp This variant has been reported in at least 37 cases of HCM, with strong segregation data. Richard et al (2003) reported this variant in one individual with HCM in their French cohort. Van Driest et al (2004) observed this variant in an HCM patient who also carried p.Gly5Arg in MYBPC3. Details regarding phase and the severity of phenotype were not reported for this patient However, a comparison of the 10 patients, including this one, with multiple variants to the patients with a single variant revealed that the multiple variant group had, on average, a more severe phenotype. Ingles et al (2005) reported observing this variant in one case of HCM. Saltzman et al (2010) reported p.Arg502Trp in 34 of 1414 (2.4%) unrelated cases of HCM, making it the most common variant in that cohort. Four families had another sarcomere variant and individuals with multiple variants were more likely to have severe clinical outcomes. They noted that ~50% of carriers of p.Arg502Trp had overt disease by age 45. They reported a combined Lod score of 4.04 and noted that the likelihood that the observed cosegregation happened by chance was 1/11,000. The highest number of family members cosegregating HCM and the variant in one individual family was three. Note that this paper includes a pedigree reported online by the Seidman group (pedigree FU). Morita et al (2008) observed the variant in two unrelated children with HCM. In one of those cases and affected parent also had the variant. One of these children also carried p.Ser858Asn in MYBPC3 (phase not reported) Note that these families may have been included in the subsequent report by Saltzman et al. Liu et al (2006) reported a Chinese patient with HCM who carried both p.Arg502Trp and IVS27+12C>T, also in MYBPC3. The arginine at codon 502 is highly conserved across species. This mutation results in a non-conservative amino acid change of a positively charged Arginine residue with a non-polar Tryptophan. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Another variant at the same codon has been reported in association with HCM (p.Arg502Gln, which we consider very likely disease causing), as have variants in nearby codons (p.Arg495Gln, p.Lys505del, p.Gly507Arg). In total the variant has not been seen in ~395 published controls, including 100 (Richard et al 2003), 200 (van Driest et al 2004), 95 (Saltzman et al 2010). The variant was observed in 1 of 3472 Caucasians and 0 of 1826 African Americans in the NHLBI Exome Sequence Project dataset (as of 7/8/2014). Individual phenotypes from that dataset are not available. Several different cohorts from studies on common complex cardiovascular disease were pooled to create that sample. There is no variant at codon 502 listed in dbSNP or 1000 genomes (as of 7/8/2014). -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 18, 2022	PP3, PM2_supporting, PS4 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 29, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MYBPC3: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PS3:Supporting -
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	Jan 17, 2020	Published functional studies using cardiomyocytes derived from induced pluripotent stem cells demonstrate R502W alters protein function (Cohn et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18809796, 25637381, 28166811, 28615295, 22267749, 25058872, 19574547, 22589294, 20378854, 12707239, 27625337, 23711808, 27639548, 28138913, 27532257, 21310275, 27831900, 23299917, 24055113, 27000522, 28420666, 15519027, 25132132, 23396983, 23642604, 29121657, 30554920, 30316040, 31006259, 30471092, 31447099, 31980526, 33500567, 34011823, 33906374, 32686758, 33673806, 32746448, 34088380) -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 16, 2016	- -

Hypertrophic cardiomyopathy 4 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Apr 23, 2024	ACMG Criteria: PP1_S,PP5,PM1,PM2_P,PM3,PM5,PS3; Variant was found in heterozygous state -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 11, 2017	This c.1504C>T (p.Arg502Trp) variant has been reported in multiple patients with hypertrophic cardiomyopathy (HCM) [PMID 1270723, 22589294, 23396983, 20378854, 23642604]. The variant was detected in 34 individuals from a large study of 1,414 unrelated HCM patients [PMID 20378854]. From this study, it was estimated that this variant conveys a 340-fold increased risk for HCM by 45 years and the clinical prognosis worsens when this c.1504C>T (p.Arg502Trp) change occurs in the setting of a pathogenic variant in another sarcomere protein gene [PMID 20378854]. This variant is common among HCM patients, occurring in an estimated 2.4% of patients [PMID 20378854]. This variant was reported in 3 heterozygous individuals in the ExAC database (http://exac.broadinstitute.org/variant/11-47364249-G-A). Arginine at position 502 of the MYBPC3 protein is highly conserved in mammals. While not validated for clinical use, computer-based algorithms predict this p.Arg502Trp change to be deleterious. This variant is thus classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 11, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 27, 2022	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Dec 30, 2019	- -

Hypertrophic cardiomyopathy Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 08, 2023	The p.Arg502Trp variant in MYBPC3 is a known pathogenic variant for hypertrophic cardiomyopathy (HCM). It has been reported across multiple studies in >150 individuals with HCM and has been shown to segregate with disease in multiple families (Richard 2003 PMID: 12707239, Van Driest 2004 PMID: 15519027, Carballo 2005 abstract, Ingles 2005 PMID: 16199542, Maron 2008 PMID: 18809796, Kaski 2009 PMID: 20031618, Marston 2009 PMID: 19574547, Saltzman 2010 PMID: 20378854, Walsh 2016 PMID: 27532257, LMM data, ClinVar Variation ID 42540). It has also been identified in 0.02% (11/68032) European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Please note that for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4, PP1_Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces arginine with tryptophan at codon 502 in the Ig-like domain C3 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant causes a loss of protein function with no evidence of the transcript or protein degradation and may alter kinetics of cardiac muscle contraction and relaxation (PMID: 30554920). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). This variant is known to be the most common pathogenic mutation in a diverse cohort of individuals affected with hypertrophic cardiomyopathy, occurring in 2.4% (34/1414) of the probands in one large study (PMID: 20378854). This variant has been shown to segregate with hypertrophic cardiomyopathy in over 25 families (PMID: 9562578, 20378854, 22386539). This variant has been reported in multiple unrelated affected individuals, including children with severe phenotype (PMID: 12707239, 22555271, 23054336, 23396983, 23711808, 27532257, 29121657, 35653365). This variant causes an estimated 340-fold increased risk for hypertrophic cardiomyopathy by 45 years of age, when more than 50% of carriers have overt disease (PMID: 20378854). This variant has been identified in 13/280632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg502Gln, is pathogenic (Clinvar variation ID 42540), indicating that the arginine residue at this position is important for MYBPC3 protein function. Based on the available evidence, this variant is classified as Pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 502 of the MYBPC3 protein (p.Arg502Trp). This variant is present in population databases (rs375882485, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 20378854, 22267749, 23396983). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42540). 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. This variant disrupts the p.Arg502 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9562578, 22386539). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 13, 2023	This missense variant replaces arginine with tryptophan at codon 502 in the Ig-like domain C3 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant causes a loss of protein function with no evidence of the transcript or protein degradation and may alter kinetics of cardiac muscle contraction and relaxation (PMID: 30554920). This variant is known to be the most common pathogenic mutation in a diverse cohort of individuals affected with hypertrophic cardiomyopathy, occurring in 2.4% (34/1414) of the probands in one large study (PMID: 20378854). This variant has been shown to segregate with hypertrophic cardiomyopathy in over 25 families (PMID: 9562578, 20378854, 22386539). This variant has been reported in multiple unrelated affected individuals, including children with severe phenotype (PMID: 12707239, 22555271, 23054336, 23396983, 23711808, 27532257, 29121657, 35653365). This variant has been identified in 13/280632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg502Gln, is pathogenic (Clinvar variation ID 42540), indicating that the arginine residue at this position is important for MYBPC3 protein function. Based on the available evidence, this variant is classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 16, 2021	The p.R502W pathogenic mutation (also known as c.1504C>T), located in coding exon 17 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1504. The arginine at codon 502 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration is one of the most common pathogenic mutations in MYBPC3. This mutation has been reported in multiple unrelated patients with hypertrophic cardiomyopathy (HCM), including individuals with pediatric and adult-onset HCM, and in several individuals with multiple sarcomeric gene mutations, and has been reported to segregate with disease in families (Richard P et al. Circulation. 2003;107(17):2227-32; Van Driest SL et al. J Am Coll Cardiol. 2004;44(9):1903-10; Saltzman AJ et al. Circ Res. 2010;106(9):1549-52; Kaski JP et al. Circ Cardiovasc Genet. 2012;5(3):317-26). This mutation is in the C3 domain of cMyBP-C and alters the electrostatic properties, which may disrupt protein-protein interactions (Zhang XL et al. Biochemistry. 2014;53(32):5332-42). In addition, other alterations affecting this amino acid (p.R502Q, c.1505G>A and p.R502G, c.1504C>G) have been previously reported in association with HCM (Niimura H et al. N Engl J Med. 1998;338(18):1248-57; Liu X et al. Sci Rep. 2015;5:11411). Based on the supporting evidence, p.R502W is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 26, 2016	Variant summary: The MYBPC3 c.1504C>T (p.Arg502Trp) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/122664 control chromosomes at a frequency of 0.0000245, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). This variant has been reported in numerous HCM patients, with evidence of co-segregation of variant with disease in some of the families. Structure study predicted the R502W mutation and other HCM-linked mutations found within the same C3 domain, may directly disrupt the interaction of cMyBP-C with other sarcomeric proteins (Zhang_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. It is the most common pathogenic HCM variant identified by our laboratory. Taken together, this variant is classified as pathogenic. -

MYBPC3-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 28, 2023	PS3_Moderate, PS4, PM5, PP1, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 07, 2018	The MYBPC3 c.1504C>T (p.Arg502Trp) missense variant is well documented as a pathogenic variant for hypertrophic cardiomyopathy (HCM). Across a selection of the available literature, the p.Arg502Trp variant has been identified in heterozygous state in at least 44 individuals diagnosed with HCM. Two of the individuals carried another variant in the MYBPC3 gene in a compound heterozygous state with the p.Arg502Trp variant, and another 11 carried an additional variant in either MYBPC3 or another sarcomere gene (Richard et al. 2003; Van Driest et al. 2004; Ingles et al. 2005; Maron et al. 2008; Marston et al. 2009; Saltzman et al. 2010; Kaski et al. 2012; Lopes et al. 2013; Camuglia et al. 2013). The Arg502Trp variant has also been reported in a heterozygous state in three individuals diagnosed with left ventricular noncompaction cardiomyopathy. One of the individuals was the son of a female proband with HCM who also carried the variant in a heterozygous state. The two other individuals were the brother and nephew of another proband with HCM who also carried the variant in a heterozygous state (Camuglia et al. 2013). The p.Arg502Trp variant was absent from 945 controls (Van Driest et al. 2004; Saltzman et al. 2010) and is reported at a frequency of 0.0001026 in the European (non-Finnish) population of the Genome Aggregation Database. The variant has been shown to segregate with disease in multiple families (Saltzman et al. 2010). Based on the collective evidence, the p.Arg502Trp variant is classified as pathogenic for MYBPC3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Hypertrophic cardiomyopathy 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 18, 2019	- -
Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Mar 16, 2017	The MYBPC3 Arg502Trp s a well known cause of HCM, being reported in multiple HCM cases worldwide and segregating with HCM in families (see Ross et al. Circulation CV Genetics, 2017). The variant is present in the Exome Aggregation Consortium dataset (MAF=0.000025; http://exac.broadinstitute.org/). We have identified this variant in 14 HCM families with some segregation data (total of 7 meiosis). Computational tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. In summary, based on segregation, extensive reports of HCM cases with the variant and rarity in the general population, we classify MYBPC3 Arg502Trp as "Pathogenic". -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 07, 2019

The p.Arg502Trp variant (rs375882485) is a well-known causative variant reported in multiple individuals with hypertrophic cardiomyopathy (HCM; Richard 2003, Maron 2008, Kaski 2012, and Lopez 2013), and shown to segregate with disease in at least one affected family (Camuglia 2013). In one large study, the p.Arg502Trp variant was identified in 2.4% of Caucasian HCM patients (Saltzman 2010). This variant was also found at 1.4% in 6179 individuals diagnosed with HCM (Walsh 2017). Nuclear magnetic resonance studies indicate that p.Arg502Trp may impair important electrostatic interactions between MYBPC3 protein and other sarcomeric proteins (Zhang 2014). Thus, the p.Arg502Trp variant meets our criteria for classification as pathogenic. -

Left ventricular noncompaction 10 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

KTest Genetics, KTest

-

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

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

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Pathogenic and reported on 07-02-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
CardioboostCm	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D;T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.5	H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.6	D;.;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.91
MVP		0.90
MPC		0.85
ClinPred		0.91	D
GERP RS		4.6
Varity_R		0.72
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs375882485; hg19: chr11-47364249;