rs111473291
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_002471.4(MYH6):c.5458C>T(p.Arg1820Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,486 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 (★★).
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000026 ( 0 hom. )
Consequence
MYH6
NM_002471.4 missense
NM_002471.4 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 2.76
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 -3 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.802
BS2
High AC in GnomAd4 at 28 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.5458C>T | p.Arg1820Trp | missense_variant | Exon 36 of 39 | ENST00000405093.9 | NP_002462.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000177 AC: 27AN: 152248Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
27
AN:
152248
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251430Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135904
GnomAD3 exomes
AF:
AC:
15
AN:
251430
Hom.:
AF XY:
AC XY:
5
AN XY:
135904
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461120Hom.: 0 Cov.: 34 AF XY: 0.0000234 AC XY: 17AN XY: 726856
GnomAD4 exome
AF:
AC:
38
AN:
1461120
Hom.:
Cov.:
34
AF XY:
AC XY:
17
AN XY:
726856
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.000184 AC: 28AN: 152366Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74508
GnomAD4 genome
AF:
AC:
28
AN:
152366
Hom.:
Cov.:
33
AF XY:
AC XY:
11
AN XY:
74508
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
2
ESP6500EA
AF:
AC:
0
ExAC
AF:
AC:
8
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 28, 2024 | 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: 31983221, 32746448) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 19, 2015 | The p.Arg1820Trp variant in MYH6 has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.1% (8/10400) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs111473291). Computational prediction tools and conservation analysis s uggest that the variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, the clinical significan ce of the p.Arg1820Trp variant is uncertain. - |
Hypertrophic cardiomyopathy 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 17, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1820 of the MYH6 protein (p.Arg1820Trp). This variant is present in population databases (rs111473291, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32746448). ClinVar contains an entry for this variant (Variation ID: 228897). 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 with a positive 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 submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 22, 2021 | - - |
MYH6-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 23, 2023 | The MYH6 c.5458C>T variant is predicted to result in the amino acid substitution p.Arg1820Trp. This variant was reported as uncertain significance in an individual with dilated cardiomyopathy (Table S2, Burstein et al. 2021. PubMed ID: 32746448). This variant is reported in 0.072% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23853758-G-A). 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 submitter | clinical testing | Ambry Genetics | Jul 28, 2022 | The p.R1820W variant (also known as c.5458C>T), located in coding exon 34 of the MYH6 gene, results from a C to T substitution at nucleotide position 5458. The arginine at codon 1820 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort; however, clinical details were limited (Burstein DS et al. Pediatr Res, 2021 05;89:1470-1476). This amino acid position is well 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at