rs730880915
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP2PP3_Moderate
The NM_000257.4(MYH7):c.5065C>T(p.Arg1689Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,614,008 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. R1689H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.5065C>T | p.Arg1689Cys | missense_variant | 35/40 | ENST00000355349.4 | |
MHRT | NR_126491.1 | n.153G>A | non_coding_transcript_exon_variant | 2/6 | |||
MYH7 | NM_001407004.1 | c.5065C>T | p.Arg1689Cys | missense_variant | 34/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.5065C>T | p.Arg1689Cys | missense_variant | 35/40 | 1 | NM_000257.4 | P1 | |
ENST00000557368.1 | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152132Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251312Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135834
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461876Hom.: 0 Cov.: 34 AF XY: 0.0000220 AC XY: 16AN XY: 727240
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74304
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 09, 2023 | This missense variant replaces arginine with cysteine at codon 1689 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 32163302, 33495597). This variant has been identified in 6/282678 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 03, 2023 | This missense variant replaces arginine with cysteine at codon 1689 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 32163302, 33495597). This variant has been identified in 6/282678 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 26, 2024 | Variant summary: MYH7 c.5065C>T (p.Arg1689Cys) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251312 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5065C>T has been reported in the literature as a VUS in an individual affected with hypertrophic cardiomyopathy who carried an additional MYBPC3 variant (e.g. Harper_2020). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32163302). ClinVar contains an entry for this variant (Variation ID: 181394). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 02, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 18, 2021 | Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID 181394; Landrum et al., 2016); 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: 32163302) - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 05, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1689 of the MYH7 protein (p.Arg1689Cys). This variant is present in population databases (rs730880915, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 181394). An algorithm developed specifically for the MYH7 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 18, 2023 | The p.R1689C variant (also known as c.5065C>T), located in coding exon 33 of the MYH7 gene, results from a C to T substitution at nucleotide position 5065. The arginine at codon 1689 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant co-occurred with an MYBPC3 variant in an individual from a hypertrophic cardiomyopathy cohort (Harper AR et al. Circ Genom Precis Med, 2020 Jun;13:e002783). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at