11-47342914-C-T

Position:

chr11-47342914-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The NM_000256.3(MYBPC3):c.1373G>A(p.Arg458His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,611,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R458C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 1.74

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 Uncertain_significance. Variant got 1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000256.3

BP4

Computational evidence support a benign effect (MetaRNN=0.27706295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.1373G>A	p.Arg458His	missense_variant	16/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.1373G>A	p.Arg458His	missense_variant	16/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.1373G>A	p.Arg458His	missense_variant	15/34	5		A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.1373G>A	p.Arg458His	missense_variant, NMD_transcript_variant	16/27	5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152238

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000490

AC:

AN:

245044

Hom.:

AF XY:

0.0000601

AC XY:

AN XY:

133004

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000586

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000112

Gnomad SAS exome

AF:

0.0000332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000632

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000466

AC:

AN:

1459602

Hom.:

Cov.:

AF XY:

0.0000496

AC XY:

AN XY:

725942

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000900

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74378

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000686

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.000245

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 25, 2023	This missense variant replaces arginine with histidine at codon 458 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 21302287) and in individuals affected with dilated cardiomyopathy (PMID: 24119082, 27532257). This variant has been identified in 13/276446 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 19, 2016	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2019	The p.Arg458His variant in MYBPC3 has been identified in 1 individual with HCM and was absent from 200 Black and 200 Caucasian chromosomes (Van Driest 2004). This variant has been identified in 1/8322 European American chromosomes and 1/4076 African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/), though these could represent presymptomatic individuals. Low frequency in the general population supports pathogenicity but is not sufficient to rule out a benign role. Our laboratory has detected this variant in 2 individuals with DCM (1 infant, 1 adult). The infant’s unaffected father also carried the variant, raising suspicion whether it was solely responsible for the infant’s DCM. Additional evidence also supports a milder or benign role. Arginine at position 458 is not conserved evolution and several species (chicken, zebra finch, frog) carry the variant amino acid, suggesting that the change may be tolerated. The change was also predicted to be benign using a computational tool, which was validated by our laboratory using a set of cardiomyopathy variants with well-established clinical significance. This tool's benign interpretation is estimated to be correct 89% of the time (Jordan 2011). In summary, this variant is less likely disease causing in isolation but additional information is needed to establish its role with confidence. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MYBPC3 p.Arg458His variant was identified in the literature in two individuals with hypertrophic cardiomyopathy and one family with dilated cardiomyopathy; the variant was not identified in 200 control individuals (Driest_2004_PMID:15519027, Roncarati_2011_PMID:21302287, Merlo_2013_PMID:2411908). The variant was identified in dbSNP (ID: rs374255707) and ClinVar (classified as uncertain significance by CHEO Genetics Diagnostic Laboratory Children's Hospital of Eastern Ontario, Laboratory for Molecular Medicine and CSER _CC_NCGL, University of Washington). The variant was identified in control databases in 13 of 276446 chromosomes at a frequency of 0.00004703 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: East Asian in 2 of 19418 chromosomes (freq: 0.000103), European (non-Finnish) in 8 of 126152 chromosomes (freq: 0.000063), Latino in 2 of 34956 chromosomes (freq: 0.000057) and South Asian in 1 of 30096 chromosomes (freq: 0.000033), but was not observed in the African, Ashkenazi Jewish, European (Finnish), or Other populations. The p.Arg458 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 23, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 458 of the MYBPC3 protein (p.Arg458His). This variant is present in population databases (rs374255707, gnomAD 0.01%). This missense change has been observed in individuals with dilated cardiomyopathy or hypertrophic cardiomyopathy (PMID: 15519027, 21302287, 24119082, 27532257). ClinVar contains an entry for this variant (Variation ID: 42527). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	This missense variant replaces arginine with histidine at codon 458 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 21302287) and in individuals affected with dilated cardiomyopathy (PMID: 24119082, 27532257). This variant has been identified in 13/276446 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 01, 2021

- -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2023

The p.R458H variant (also known as c.1373G>A), located in coding exon 16 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1373. The arginine at codon 458 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in subjects with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10; Merlo M et al. Clin Transl Sci, 2013 Dec;6:424-8; Roncarati R et al. J. Cell. Physiol., 2011 Nov;226:2894-900; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Walsh R et al. Genet. Med., 2017 02;19:192-203). This alteration has also been seen in exome cohorts, but cardiovascular history was not provided (Andreasen C et al. Eur J Hum Genet. 2013;21(9):918-28; Dorschner MO et al. Am J Hum Genet. 2013;93(4):631-40; Amendola LM et al. Genome Res. 2015;25(3):305-15). This amino acid position is not well conserved in available vertebrate species, and histidine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

CardioboostCm

Benign

0.044

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

T;T;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.048

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.056

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.6

N;.;N

REVEL

Benign

0.13

Sift

Benign

0.14

T;.;T

Sift4G

Benign

0.18

T;T;T

Vest4

0.77

MVP

0.56

MPC

0.28

ClinPred

0.038

GERP RS

3.6

Varity_R

0.085

gMVP

0.40

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