rs376002621

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2

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
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH6. . Gene score misZ 0.85843 (greater than the threshold 3.09). Trascript score misZ 4.1282 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, hypertrophic cardiomyopathy, Keppen-Lubinsky syndrome, atrial septal defect 3, familial isolated dilated cardiomyopathy, hypertrophic cardiomyopathy 14.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.83
BS2
High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYH6NM_002471.4 linkuse as main transcriptc.3383G>A p.Arg1128His missense_variant 26/39 ENST00000405093.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYH6ENST00000405093.9 linkuse as main transcriptc.3383G>A p.Arg1128His missense_variant 26/395 NM_002471.4 P1

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
GnomAD3 exomes
AF:
0.0000325
AC:
8
AN:
246148
Hom.:
0
AF XY:
0.0000149
AC XY:
2
AN XY:
133944
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 SAS 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
Gnomad4 AFR exome
AF:
0.000928
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000900
Gnomad4 OTH exome
AF:
0.0000829
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
Gnomad4 AFR
AF:
0.000653
Gnomad4 AMR
AF:
0.0000655
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:
0.000479
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
Uncertain significance, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Uncertain significance, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxOct 03, 2022Has 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 -
Uncertain significance, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Skane University Hospital LundJul 19, 2023- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 30, 2013The 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
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024This 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). 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 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
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 01, 2021- -
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioOct 16, 2019- -
Left ventricular noncompaction Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteMay 23, 2017- -
MYH6-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJul 15, 2023The 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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 12, 2022The 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
MutationTaster
Benign
1.0
D;D
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

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.

Other links and lift over

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