chr11-47351481-C-T

Position:

chr11-47351481-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000256.3(MYBPC3):c.50G>A(p.Arg17Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000578 in 1,590,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R17W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.63

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22598496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.50G>A	p.Arg17Gln	missense_variant	2/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.50G>A	p.Arg17Gln	missense_variant	2/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.50G>A	p.Arg17Gln	missense_variant	2/34	5		A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.50G>A	p.Arg17Gln	missense_variant, NMD_transcript_variant	2/27	5

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000719

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:

0.000479

GnomAD3 exomes

AF:

0.0000848

AC:

AN:

235814

Hom.:

AF XY:

0.0000621

AC XY:

AN XY:

128878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000297

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:

0.0000943

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000535

AC:

AN:

1438260

Hom.:

Cov.:

AF XY:

0.0000506

AC XY:

AN XY:

710816

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000636

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000356

Gnomad4 OTH exome

AF:

0.000135

GnomAD4 genome

AF:

0.0000984

AC:

AN:

152374

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000718

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:

0.000474

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000230

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000108

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 01, 2013	The Arg17Gln variant in MYBPC3 has not been reported in individuals with cardiom yopathy, but has been identified in 1/8408 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). The affected amino acid is not well conserved in evolution, suggesting that a change may be tolerated. Other computational analyses (biochemical amino acid properties, Alig nGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impa ct to the protein. At this time, additional information is needed to fully asses s the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2024	Variant summary: MYBPC3 c.50G>A (p.Arg17Gln) results in a conservative amino acid change located in the Immunoglobulin subtype (IPR003599) of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 235814 control chromosomes. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Dilated Cardiomyopathy phenotype (3.1e-05), strongly suggesting that the variant is benign. c.50G>A has been reported in the literature in individuals affected with Cardiomyopathy, however not all the information was provided for further analysis (example, McGurk_2023, Ochoa_2018, Pottinger_2020, Viswanathan_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37652022, 30442288, 32009526, 29121657). ClinVar contains an entry for this variant (Variation ID: 164160). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 13, 2023	This missense variant replaces arginine with glutamine at codon 17 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 over ten individuals affected with hypertrophic cardiomyopathy (PMID: 19150014, 25342278, 28356264, 28771489, 29121657, 30442288, 34555931), in one individual with dilated cardiomyopathy (PMID: 30871747), and in two related individuals who were reported to be normal (PMID: 34555931). One of the affected probands also carried a pathogenic variant in the MYH7 gene that could explain the observed phenotype (PMID: 34555931). This variant has also been identified in 20/235814 chromosomes (10/33652 Latino chromosomes, 0.0297%) in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in affected individuals and has also been observed at an elevated allele frequency in the general population. 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	Aug 17, 2021	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2024	Identified in patients with cardiomyopathy in published literature; several patients harbored additional cardiogenetic variants (PMID: 19150014, 28356264, 29121657, 28771489, 28679633, 30442288, 30871747, 32009526, 34555931, 37652022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25342278, 19150014, 28356264, 29121657, 28771489, 28679633, 30442288, 30871747, 32009526, 34555931, 37652022) -

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 17 of the MYBPC3 protein (p.Arg17Gln). This variant is present in population databases (rs374630007, gnomAD 0.03%). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 25342278, 29121657, 30871747; Invitae). ClinVar contains an entry for this variant (Variation ID: 164160). 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. 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	Feb 05, 2024	This missense variant replaces arginine with glutamine at codon 17 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 over ten individuals affected with hypertrophic cardiomyopathy (PMID: 19150014, 25342278, 28356264, 28771489, 29121657, 30442288, 34555931), in one individual with dilated cardiomyopathy (PMID: 30871747), and in two related individuals who were reported to be normal (PMID: 34555931). One of the affected probands also carried a pathogenic variant in the MYH7 gene that could explain the observed phenotype (PMID: 34555931). This variant has also been identified in 20/235814 chromosomes (10/33652 Latino chromosomes, 0.0297%) in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in affected individuals and has also been observed at an elevated allele frequency in the general population. 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The p.R17Q variant (also known as c.50G>A), located in coding exon 2 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 50. The arginine at codon 17 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in subjects with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM); however, clinical details were limited and additional alterations in other cardiac-related genes were identified in some cases (García-Castro M et al. Rev Esp Cardiol, 2009 Jan;62:48-56; Alfares AA et al. Genet Med. 2015 Nov;17(11):880-8; Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Viswanathan SK et al. PLoS ONE, 2017 Nov;12:e0187948; Sousa A et al. Rev Port Cardiol, 2019 02;38:129-139; Helms AS at al. Circ Genom Precis Med. 2020 Oct;13(5):396-405). This variant was detected in both affected and unaffected relatives in a family with HCM (Dias GM et al. Circ Genom Precis Med. 2021 Oct;14(5):e003476). This amino acid position is not well conserved in available 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

0.13

CardioboostCm

Benign

0.030

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T;T

Eigen

Benign

0.015

Eigen_PC

Benign

0.057

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

L;.;.

MutationTaster

Benign

0.75

N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.87

N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.015

D;D;D

Sift4G

Uncertain

0.032

D;D;D

Polyphen

0.92

P;.;.

Vest4

0.44

MVP

0.85

MPC

0.54

ClinPred

0.17

GERP RS

3.3

Varity_R

0.16

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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