rs370362589

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM5BP4_Moderate

The NM_000256.3(MYBPC3):c.1565C>T(p.Ala522Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. A522T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.82

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 Uncertain_significance. Variant got 2 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 chr11-47342638-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.18778381).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.1565C>T	p.Ala522Val	missense_variant	17/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.1565C>T	p.Ala522Val	missense_variant	17/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.1565C>T	p.Ala522Val	missense_variant	16/34	5		A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.1565C>T	p.Ala522Val	missense_variant, NMD_transcript_variant	17/27	5

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

249088

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135148

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.0000290

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461620

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

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:

0.0000117

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000644

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.000231

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 14, 2016

The p.Ala522Val variant in MYBPC3 has not been previously reported in individual s with cardiomyopathy, but has been identified in 2/9788 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 370362589). Alanine (Ala) at position 522 is poorly conserved in evolution and t he change to valine (Val) was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimat ed to be correct 89% of the time (Jordan 2011). In summary, the clinical signifi cance of the p.Ala522Val variant is uncertain. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

MYBPC3 NM_000256.3 exon 16 p.Ala522Val (c.1565C>T): This variant has not been reported in the literature but is present in 4/23998 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs370362589). This variant is present in ClinVar (Variation ID: 264356). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2020

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22958901, 28087566, 30297972) -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 522 of the MYBPC3 protein (p.Ala522Val). This variant is present in population databases (rs370362589, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20800588, 30297972). ClinVar contains an entry for this variant (Variation ID: 264356). 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 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2023

The p.A522V variant (also known as c.1565C>T), located in coding exon 17 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1565. The alanine at codon 522 is replaced by valine, an amino acid with similar properties. This variant has been reported in a hypertrophic cardiomyopathy cohorts, and in the Jackson Heart Study cohort, though details were limited (Millat G et al. Clin Chim Acta. 2010; 411(23-24):1983-91; Bick AG et al. Am J Hum Genet. 2012; 91(3):513-9; Ho CY et al. Circulation, 2018 Oct;138:1387-1398). 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 variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

CardioboostCm

Benign

0.0024

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.44

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.32

T;T;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.28

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

2.0

M;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.6

N;.;N

REVEL

Benign

0.042

Sift

Benign

0.039

D;.;D

Sift4G

Benign

0.24

T;T;T

Vest4

0.33

MVP

0.79

MPC

0.33

ClinPred

0.059

GERP RS

2.6

Varity_R

0.075

gMVP

0.50

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