rs1025146248

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PP3

The NM_002471.4(MYH6):c.2578C>T(p.Arg860Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,614,028 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R860H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.63

Variant links:

Genes affected

MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]

MYH6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP2

Missense variant where missense usually causes diseases, MYH6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4 linkuse as main transcript	c.2578C>T	p.Arg860Cys	missense_variant	21/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9 linkuse as main transcript	c.2578C>T	p.Arg860Cys	missense_variant	21/39	5	NM_002471.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152138

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251484

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000251

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 14

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 23, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH6 protein function. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 860 of the MYH6 protein (p.Arg860Cys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with restrictive cardiomyopathy or hypertrophic cardiomyopathy (PMID: 25351510, 29907873). ClinVar contains an entry for this variant (Variation ID: 470516). -

Dilated cardiomyopathy 1EE;C2750467:Hypertrophic cardiomyopathy 14;C3279790:Atrial septal defect 3;C3279791:Sick sinus syndrome 3, susceptibility to;C3495498:Hypertrophic cardiomyopathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 12, 2021

- -

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

May 09, 2017

Given that this variant has not been reported in the literature, and its uncertain association with hypertrophic cardiomyopathy, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has not been reported in the literature. It is not present in ClinVar. The arginine at codon 860 is not conserved across species, and neither are neighboring amino acids. The variant was reported online in 1 of 123,131 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 55,855 individuals of European descent (MAF=0.0009%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2024

The p.R860C variant (also known as c.2578C>T), located in coding exon 19 of the MYH6 gene, results from a C to T substitution at nucleotide position 2578. The arginine at codon 860 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;D

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.51

LIST_S2

Pathogenic

0.99

D;.

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.98

D;D

Vest4

0.63

MutPred

0.57

Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);

MVP

0.94

MPC

1.0

ClinPred

0.97

GERP RS

3.6

Varity_R

0.37

gMVP

0.78

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