chr14-23383292-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_002471.4(MYH6):c.5594G>A(p.Arg1865Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000921 in 1,324,786 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. R1865W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000041 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 7.88

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy 14
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
Keppen-Lubinsky syndrome
Inheritance: AD Classification: MODERATE Submitted by: Illumina
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
atrial septal defect 3
Inheritance: AD Classification: LIMITED Submitted by: G2P
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
hypertrophic cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MYH6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.859

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4 link	c.5594G>A	p.Arg1865Gln	missense_variant	Exon 37 of 39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9 link	c.5594G>A	p.Arg1865Gln	missense_variant	Exon 37 of 39	5	NM_002471.4	ENSP00000386041.3		P13533
MYH6	ENST00000651452.1 link	n.821G>A		non_coding_transcript_exon_variant	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000406

AC:

AN:

123126

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:

0.0000798

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000677

AC:

AN:

251182

AF XY:

0.0000663

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000974

AC:

117

AN:

1201660

Hom.:

Cov.:

AF XY:

0.0000891

AC XY:

AN XY:

594836

show subpopulations

African (AFR)

AF:

0.0000757

AC:

AN:

26418

American (AMR)

AF:

0.0000535

AC:

AN:

37404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16970

East Asian (EAS)

AF:

0.000173

AC:

AN:

17338

South Asian (SAS)

AF:

0.00

AC:

AN:

83226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3538

European-Non Finnish (NFE)

AF:

0.000115

AC:

108

AN:

939978

Other (OTH)

AF:

0.0000458

AC:

AN:

43684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000406

AC:

AN:

123126

Hom.:

Cov.:

AF XY:

0.0000175

AC XY:

AN XY:

57194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32208

American (AMR)

AF:

0.00

AC:

AN:

9558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3266

East Asian (EAS)

AF:

0.00

AC:

AN:

3678

South Asian (SAS)

AF:

0.00

AC:

AN:

3534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

260

European-Non Finnish (NFE)

AF:

0.0000798

AC:

AN:

62674

Other (OTH)

AF:

0.00

AC:

AN:

1706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000203

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 14

Uncertain:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1865 of the MYH6 protein (p.Arg1865Gln). This variant is present in population databases (rs138720701, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital heart defects (PMID: 20656787). ClinVar contains an entry for this variant (Variation ID: 520531). 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. -

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

Oct 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Mar 13, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with hypertrophic cardiomyopathy (HCM) who harbored an additional cardiogenetic variant and in a patient with secundum atrial septal defect (PMID: 23396983, 20656787); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25351510, 20656787, 29762087, 35621855, 22955375, 29687901, 23396983) -

MYH6-related disorder

Uncertain:1

Dec 20, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The MYH6 c.5594G>A variant is predicted to result in the amino acid substitution p.Arg1865Gln. This variant was reported in an individual with hypertrophic cardiomyopathy (Table S1, Lopes et al. 2013. PubMed ID: 23396983). This variant was also reported in a family with a wide spectrum of congenital heart defects, including atrial septal defect, ventricular septal defect, and dilated inferior vena cava. However, this variant was also identified in an unaffected family member (Granados-Riveron et al. 2010. PubMed ID: 20656787). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Aug 30, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R1865Q variant (also known as c.5594G>A), located in coding exon 35 of the MYH6 gene, results from a G to A substitution at nucleotide position 5594. The arginine at codon 1865 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected in an individual with a secundum atrial septal defect, as well as in his mother with dilated inferior vena cava, in his brother with a small ventricular septal defect that closed spontaneously, and in his unaffected sister; of note, MYH6 was the only gene tested in this family (Granados-Riveron JT et al. Hum. Mol. Genet., 2010 Oct;19:4007-16). This alteration has also been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

D;D

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;.

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

2.0

M;M

PhyloP100

7.9

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.6

D;D

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.41

T;T

Polyphen

0.99

D;D

Vest4

0.91

MVP

0.80

MPC

0.91

ClinPred

0.47

GERP RS

4.5

Varity_R

0.47

gMVP

0.46

Mutation Taster

=21/79

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over