ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5779A>T (p.Ile1927Phe)

gnomAD frequency: 0.00006  dbSNP: rs767300277
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000623784 SCV000740379 uncertain significance Primary familial hypertrophic cardiomyopathy 2017-07-13 criteria provided, single submitter clinical testing
Invitae RCV001068143 SCV001233234 uncertain significance Hypertrophic cardiomyopathy 2024-01-21 criteria provided, single submitter clinical testing 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.
Color Diagnostics, LLC DBA Color Health RCV001181572 SCV001346749 uncertain significance Cardiomyopathy 2023-03-08 criteria provided, single submitter clinical testing 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.
GeneDx RCV001566832 SCV001790410 uncertain significance not provided 2022-02-11 criteria provided, single submitter clinical testing 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)
Ambry Genetics RCV002358637 SCV002652209 uncertain significance Cardiovascular phenotype 2023-04-26 criteria provided, single submitter clinical testing 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; G&oacute;mez 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, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity Omics RCV001566832 SCV003817708 uncertain significance not provided 2022-01-10 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001181572 SCV004239491 uncertain significance Cardiomyopathy 2023-03-06 criteria provided, single submitter clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000656224 SCV000678418 uncertain significance Wolff-Parkinson-White pattern 2017-07-14 no assertion criteria provided research This variant was identified in an individual with Wolff-Parkinson-White syndrome
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001566832 SCV001975152 uncertain significance not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.