chr14-23413770-T-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1PP2BP4_Moderate
The NM_000257.4(MYH7):c.5779A>T(p.Ile1927Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000427 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I1927I) has been classified as Likely benign.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.5779A>T | p.Ile1927Phe | missense_variant | 39/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.5779A>T | p.Ile1927Phe | missense_variant | 38/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.5779A>T | p.Ile1927Phe | missense_variant | 39/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251320Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135860
GnomAD4 exome AF: 0.0000438 AC: 64AN: 1461822Hom.: 0 Cov.: 32 AF XY: 0.0000468 AC XY: 34AN XY: 727210
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74364
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 06, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 08, 2023 | This missense variant replaces isoleucine with phenylalanine at codon 1927 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in multiple unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 18409188, 20624503, 20800588, 21239446, 23140321, 27574918, 28771489, 30696458, 32268277, 33495597). One of these individuals also carried another pathogenic variant in the MYBPC3 gene (PMID: 20624503). This variant has been reported in three related individuals (PMID: 26497160). Two of them were affected with hypertrophic cardiomyopathy, and also carried a pathogenic variant in the MYL2 gene that could explain the observed phenotype. The other carrier in the family was not diagnosed with cardiovascular disease. This variant has been reported in an individual affected with limb-girdle muscular dystrophy with no cardiac involvement (PMID: 25214167, 27387980). This variant has also been identified in 13/282718 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, although this variant has been reported in multiple affected individuals, it has also been reported in individuals carrying different pathogenic variants that could explain the observed disease, as well as in individuals with no cardiac involvement. 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 | Jan 11, 2024 | This missense variant replaces isoleucine with phenylalanine at codon 1927 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in multiple unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 18409188, 20624503, 20800588, 21239446, 23140321, 27574918, 28771489, 30696458, 32268277, 33495597). One of these individuals also carried another pathogenic variant in the MYBPC3 gene (PMID: 20624503). This variant has been reported in three related individuals (PMID: 26497160). Two of them were affected with hypertrophic cardiomyopathy, and also carried a pathogenic variant in the MYL2 gene that could explain the observed phenotype. The other carrier in the family was not diagnosed with cardiovascular disease. This variant has been reported in an individual affected with limb-girdle muscular dystrophy with no cardiac involvement (PMID: 25214167, 27387980). This variant has also been identified in 13/282718 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, although this variant has been reported in multiple affected individuals, it has also been reported in individuals carrying different pathogenic variants that could explain the observed disease, as well as in individuals with no cardiac involvement. 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 provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 10, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 11, 2022 | Observed in multiple individuals with HCM in the published literature and at GeneDx, however, at least one family harbored a co-occurring pathogenic variant (Fokstuen et al, 2008; Millat et al, 2010; Claes et al., 2016; Gomez et al., 2017); Reported in an individual with childhood onset axial and distal limb weakness and no cardiac involvement or known family history (Fiorillo et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28356264, 21239446, 20624503, 27387980, 32268277, 26497160, 25214167, 18409188) - |
Wolff-Parkinson-White pattern Uncertain:1
Uncertain significance, no assertion criteria provided | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Jul 14, 2017 | This variant was identified in an individual with Wolff-Parkinson-White syndrome - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jul 13, 2017 | - - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1927 of the MYH7 protein (p.Ile1927Phe). This variant is present in population databases (rs767300277, gnomAD 0.009%). This missense change has been observed in individual(s) with myopathy and HCM (PMID: 18409188, 20624503, 27387980, 28356264). ClinVar contains an entry for this variant (Variation ID: 487639). 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 MYH7 protein function with a negative predictive value of 95%. 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 | Apr 26, 2023 | The p.I1927F variant (also known as c.5779A>T), located in coding exon 37 of the MYH7 gene, results from an A to T substitution at nucleotide position 5779. The isoleucine at codon 1927 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in several hypertrophic cardiomyopathy cohorts, and sometimes in individuals who had variants in other cardiac-related genes (Fokstuen S et al. Hum. Mutat. 2008;29:879-85; Millat G et al. Eur J Med Genet;53:261-7; Teirlinck CH et al. BMC Med. Genet. 2012;13:105; Lopes LR et al. Heart. 2015;101:294-301; Claes GR et al. Eur. Heart J. 2016;37:1815-22; Jaafar N et al. Genet Test Mol Biomarkers, 2016 Nov;20:674-679; Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10:[ePub ahead of print]). This variant was also detected in an individual with axial and distal upper and lower limb weakness but no cardiac involvement (Fiorillo C et al. Orphanet J Rare Dis. 2016;11:91). This amino acid position is not well 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at