rs376002621

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BS1_SupportingBS2

The NM_002471.4(MYH6):​c.3383G>A​(p.Arg1128His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000478 in 1,611,036 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. R1128C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

8
6
5

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11

Conservation

PhyloP100: 7.70

Publications

4 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.83
BS1
Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000329 (48/1459094) while in subpopulation AFR AF = 0.000928 (31/33406). AF 95% confidence interval is 0.000672. There are 0 homozygotes in GnomAdExome4. There are 21 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH6NM_002471.4 linkc.3383G>A p.Arg1128His missense_variant Exon 26 of 39 ENST00000405093.9 NP_002462.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH6ENST00000405093.9 linkc.3383G>A p.Arg1128His missense_variant Exon 26 of 39 5 NM_002471.4 ENSP00000386041.3 P13533

Frequencies

GnomAD3 genomes
AF:
0.000191
AC:
29
AN:
151942
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000653
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.000479
GnomAD2 exomes
AF:
0.0000325
AC:
8
AN:
246148
AF XY:
0.0000149
show subpopulations
Gnomad AFR exome
AF:
0.000468
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000329
AC:
48
AN:
1459094
Hom.:
0
Cov.:
35
AF XY:
0.0000289
AC XY:
21
AN XY:
725900
show subpopulations
African (AFR)
AF:
0.000928
AC:
31
AN:
33406
American (AMR)
AF:
0.00
AC:
0
AN:
44636
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26098
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39618
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86120
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51584
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5692
European-Non Finnish (NFE)
AF:
0.00000900
AC:
10
AN:
1111608
Other (OTH)
AF:
0.0000829
AC:
5
AN:
60332
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
5
10
16
21
26
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.000191
AC:
29
AN:
151942
Hom.:
0
Cov.:
31
AF XY:
0.000189
AC XY:
14
AN XY:
74196
show subpopulations
African (AFR)
AF:
0.000653
AC:
27
AN:
41324
American (AMR)
AF:
0.0000655
AC:
1
AN:
15260
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4802
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10578
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68008
Other (OTH)
AF:
0.000479
AC:
1
AN:
2086
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.494
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000201
Hom.:
0
Bravo
AF:
0.000204
ESP6500AA
AF:
0.000458
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:4
-
Clinical Genetics, Academic Medical Center
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Oct 03, 2022
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Jul 19, 2023
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not specified Uncertain:1
Jan 30, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The Arg1128His variant in MYH6 has not been reported in the literature nor previ ously identified by our laboratory. This variant has been identified in 2/4370 o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS/). Computational analyses (bioche mical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) sugge st that the Arg1128His variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. Additional information is n eeded to fully assess the clinical significance of the Arg1128His variant. -

Hypertrophic cardiomyopathy 14 Uncertain:1
Nov 04, 2024
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 histidine, which is basic and polar, at codon 1128 of the MYH6 protein (p.Arg1128His). This variant is present in population databases (rs376002621, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 44482). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYH6 protein function with a negative predictive value of 80%. 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
Sep 01, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Cardiomyopathy Uncertain:1
Oct 16, 2019
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Left ventricular noncompaction Uncertain:1
May 23, 2017
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

MYH6-related disorder Uncertain:1
Jul 15, 2023
PreventionGenetics, part of Exact Sciences
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The MYH6 c.3383G>A variant is predicted to result in the amino acid substitution p.Arg1128His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.055% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23859615-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype Uncertain:1
Aug 12, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.3383G>A (p.R1128H) alteration is located in exon 26 (coding exon 24) of the MYH6 gene. This alteration results from a G to A substitution at nucleotide position 3383, causing the arginine (R) at amino acid position 1128 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
-0.031
T
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.78
D;D
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.72
T;.
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.83
D;D
MetaSVM
Uncertain
0.77
D
MutationAssessor
Pathogenic
3.2
M;M
PhyloP100
7.7
PrimateAI
Pathogenic
0.81
D
PROVEAN
Uncertain
-3.3
D;D
REVEL
Pathogenic
0.75
Sift
Benign
0.059
T;T
Sift4G
Uncertain
0.011
D;D
Polyphen
1.0
D;D
Vest4
0.76
MVP
0.98
MPC
3.5
ClinPred
0.73
D
GERP RS
4.3
Varity_R
0.17
gMVP
0.60
Mutation Taster
=25/75
disease causing

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

Other links and lift over

dbSNP: rs376002621; hg19: chr14-23859615; COSMIC: COSV62449258; COSMIC: COSV62449258; API