11-47337729-A-G

Position:

chr11-47337729-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1PM1PP3_StrongPP5_Very_Strong

The NM_000256.3(MYBPC3):c.2374T>C(p.Trp792Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000448 in 1,563,840 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W792L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 5.82

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 18 ACMG points.

PS1

Transcript NM_000256.3 (MYBPC3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 578612

PM1

In a domain Fibronectin type-III 1 (size 96) in uniprot entity MYPC3_HUMAN there are 50 pathogenic changes around while only 6 benign (89%) in NM_000256.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 11-47337729-A-G is Pathogenic according to our data. Variant chr11-47337729-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47337729-A-G is described in Lovd as [Pathogenic]. Variant chr11-47337729-A-G 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.2374T>C	p.Trp792Arg	missense_variant	24/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.2374T>C	p.Trp792Arg	missense_variant	24/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.2374T>C	p.Trp792Arg	missense_variant	23/34	5		A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.2374T>C	p.Trp792Arg	missense_variant, NMD_transcript_variant	24/27	5

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151760

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000480

GnomAD4 exome

AF:

0.00000212

AC:

AN:

1412080

Hom.:

Cov.:

AF XY:

0.00000287

AC XY:

AN XY:

697906

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000276

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151760

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74092

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000480

Alfa

AF:

0.00118

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.00000857

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary familial hypertrophic cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 30, 2023	Variant summary: MYBPC3 c.2374T>C (p.Trp792Arg) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 172418 control chromosomes. c.2374T>C has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g., van Driest_2004, Theis_2009, Pan_2012, Ho_2018). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (e.g., Smelter_2018, Helms_2020). Mouse cardiomyocytes harboring the variant protein were found to display reduced cMyBP-C protein levels and contractile kinetics similar to cells lacking endogenous cMyBP-C (Smelter_2018). The variant was also shown to contribute to protein instability (Smelter_2018, Helms_2020). Six ClinVar submitters (evaluation after 2014) have classified the variant as pathogenic (n = 3) or likely pathogenic (n = 3). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 21, 2015	- -

not provided

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 07, 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. p.Trp792Arg in the MYBPC3 gene. Given sufficient case data and lack in the general population, we consider this variant likely disease causing and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has been seen in at least 8 unrelated individuals with HCM (not including this patient). The one published case was reported by Van Driest et al (2004), who identified the variant in 1 of 389 individuals studied with HCM. Segregation data was not reported in this study. The same group later reported this variant in two individuals, though it is unclear if they were related to each or if one of them overlaps with the prior report (Theis et al 2009). There are no other reported missense variants at this codon or within 10 codons of position 792 (Cardiogenomics, Google, Van Driest et al 2004). This is a non conservative amino acid change with a non polar, neutral Tryptophan replaced with a polar, positive Arginine. Tryptophan is conserved at codon 792 across species. In silico analysis (PolyPhen) predicts the amino acid change to be probably damaging to protein structure/function, and Mutation Taster predicts disease-causing. Analysis with a sarcomere-specific PolyPhen tool predicts the variant to be pathogenic. In total, the variant has been seen in 1 of 6,596 published controls, laboratory controls, and publicly available general population samples. It was not seen in 200 ethnically diverse control individuals analyzed by Van Driest et al (2004). GeneDx did not see this variant in 100 Caucasian individuals and 100 African American individuals. The variant was recently reported online in 1 of 4158 European-American individuals and 0 of 2038 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of Oct. 19, 2013). The phenotype of that individual is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Of note, other HCM-causing variants have been seen at similar frequencies in that dataset. There is no missense variation at codon 792 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of Oct 19, 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2022	Published functional studies demonstrate a damaging effect resulting in abnormal contractile kinetics and reduced protein stability (Smelter et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 36605); This variant is associated with the following publications: (PMID: 27114410, 34135346, 15519027, 23074333, 23299917, 24793961, 26914223, 29451820, 19808356, 25637381, 27532257, 29540445, 32841044, 31447099, 33782553) -

Hypertrophic cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 26, 2022	The p.Trp792Arg variant in MYBPC3 has been previously identified in at least 19 individuals with HCM and segregated with disease in 1 affected relative (Theis 2009 PMID: 19808356, Pan 2012 PMID: 23074333, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 36605) and have been identified in 0.004% (3/67954) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). Animal models in mice have shown that this variant affects protein function (Smelter 2018 PMID: 29451820) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Trp792Arg variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3, PS3_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 792 of the MYBPC3 protein (p.Trp792Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertropic cardiomyopathy (PMID: 15519027, 19808356, 23074333, 24793961, 27532257). ClinVar contains an entry for this variant (Variation ID: 36605). An algorithm developed specifically for the MYBPC3 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). For these reasons, this variant has been classified as Pathogenic. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 13, 2021

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2023

The p.W792R variant (also known as c.2374T>C), located in coding exon 24 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 2374. The tryptophan at codon 792 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals from hypertrophic cardiomyopathy cohorts (Van Driest SL et al. J. Am. Coll. Cardiol. 2004 Nov; 44: 1903-10; Theis JL et al. Circ Heart Fail 2009 Jul;2:325-33; Bos JM et al. Mayo Clin. Proc. 2014 Jun;89:727-37; Murphy SL et al. J Cardiovasc Transl Res 2016 Apr;9:153-61; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). One study indicated this variant may result in protein destabilization and degradation (Smelter DF. Am. J. Physiol. Heart Circ. Physiol. 2018 06;314(6):H1179-H1191). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

MYBPC3-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

This variant has been previously reported as a heterozygous change in multiple individuals with hypertrophic cardiomyopathy (PMID: 15519027, 25637381, 26914223, 27532257). Functional studies in mouse cardiomyocytes have shown that this variant results in reduced protein stability (PMID: 29451820). It is absent from the gnomAD population database and thus is presumed to be rare. The c.2374T>C (p.Trp792Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.2374T>C (p.Trp792Arg) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;T;T

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

4.7

H;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-12

D;.;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.99

MVP

0.97

MPC

1.1

ClinPred

1.0

GERP RS

4.0

Varity_R

0.98

gMVP

0.96

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

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