chr14-23390361-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_002471.4(MYH6):c.3428G>A(p.Arg1143Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000392 in 1,608,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1143W) has been classified as Uncertain significance.
Frequency
Consequence
NM_002471.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.3428G>A | p.Arg1143Gln | missense_variant | 26/39 | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.3428G>A | p.Arg1143Gln | missense_variant | 26/39 | 5 | NM_002471.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000264 AC: 4AN: 151758Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000793 AC: 19AN: 239592Hom.: 0 AF XY: 0.000114 AC XY: 15AN XY: 131040
GnomAD4 exome AF: 0.0000405 AC: 59AN: 1456480Hom.: 0 Cov.: 34 AF XY: 0.0000580 AC XY: 42AN XY: 724654
GnomAD4 genome AF: 0.0000263 AC: 4AN: 151874Hom.: 0 Cov.: 31 AF XY: 0.0000539 AC XY: 4AN XY: 74260
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 29, 2015 | The p.Arg1143Gln variant in MYH6 has not been previously reported in individuals with cardiomyopathy, but has been identified in 9/15338 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs543585784). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg1143Gln variant is uncertain. - |
Hypertrophic cardiomyopathy 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1143 of the MYH6 protein (p.Arg1143Gln). This variant is present in population databases (rs543585784, gnomAD 0.04%), 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: 27930701, 28611029). ClinVar contains an entry for this variant (Variation ID: 228890). 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. - |
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MYH6 p.Arg1143Gln variant was identified in 2 of 1688 proband chromosomes (frequency: 0.00119) from one individual with cardiovascular disease and another individual with sudden unexplained death (Sanchez_2016_PMID:27930701; Haskell_2017_PMID:28611029). The variant was identified in dbSNP (ID: rs543585784) and ClinVar (classified as VUS by Illumina, Ambry Genetics and Laboratory for Molecular Medicine). The variant was not identified in COSMIC or LOVD 3.0. The variant was identified in control databases in 19 of 239592 chromosomes (0 homozygous) at a frequency of 0.000079 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 13 of 30216 chromosomes (freq: 0.00043), East Asian in 1 of 17930 chromosomes (freq: 0.000056), European (non-Finnish) in 4 of 108002 chromosomes (freq: 0.000037) and Latino in 1 of 34158 chromosomes (freq: 0.000029), but was not observed in the African, Ashkenazi Jewish, European (Finnish) or Other populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg1143 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 26, 2022 | The p.R1143Q variant (also known as c.3428G>A), located in coding exon 24 of the MYH6 gene, results from a G to A substitution at nucleotide position 3428. The arginine at codon 1143 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported once in a sudden unexplained death cohort (Sanchez O et al. PLoS ONE, 2016 Dec;11:e0167358). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Oct 27, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at