Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000037529 | SCV000061187 | uncertain significance | not specified | 2012-01-24 | criteria provided, single submitter | clinical testing | The Ala1765Thr variant (MYH6) has not been reported in the literature nor previo usly identified by our laboratory. Alanine (Ala) at position 1765 is conserved i n mammals and in evolutionarily distant species, but computational analyses (bio chemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide s trong support for or against an impact to the protein. Additional information is needed to fully assess the clinical significance of the Ala1765Thr variant. |
Invitae | RCV000467764 | SCV000546145 | uncertain significance | Hypertrophic cardiomyopathy 14 | 2024-01-22 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1765 of the MYH6 protein (p.Ala1765Thr). This variant is present in population databases (rs397516775, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28082330, 31308319). ClinVar contains an entry for this variant (Variation ID: 44533). 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 MYH6 protein function with a negative 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. |
Ambry Genetics | RCV000619201 | SCV000735750 | uncertain significance | Cardiovascular phenotype | 2021-09-16 | criteria provided, single submitter | clinical testing | The p.A1765T variant (also known as c.5293G>A), located in coding exon 34 of the MYH6 gene, results from a G to A substitution at nucleotide position 5293. The alanine at codon 1765 is replaced by threonine, an amino acid with similar properties. This variant co-occurred with variants in other cardiac-related genes in an individual with unspecified cardiomyopathy (van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309). 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. |
CHEO Genetics Diagnostic Laboratory, |
RCV000770426 | SCV000901869 | uncertain significance | Cardiomyopathy | 2017-01-04 | criteria provided, single submitter | clinical testing | |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV000845414 | SCV000987482 | uncertain significance | Primary familial hypertrophic cardiomyopathy | criteria provided, single submitter | clinical testing | ||
Fulgent Genetics, |
RCV002482989 | SCV002792892 | uncertain significance | Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to | 2021-07-26 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000037529 | SCV003922869 | likely benign | not specified | 2023-03-21 | criteria provided, single submitter | clinical testing | Variant summary: MYH6 c.5293G>A (p.Ala1765Thr) results in a non-conservative amino acid change located in the myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251412 control chromosomes, predominantly at a frequency of 0.00021 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Hypertrophic Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.5293G>A has been reported in the literature as a VUS in settings of multigene panel testing in at least two individuals affected with Hypertrophic Cardiomyopathy and in an individual affected with an unknown/unspecified cardiomyopathy (e.g. Walsh_2017, Tran_2019, van Lint_2019). These reports do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. |
Clinical Genetics, |
RCV001699024 | SCV001920798 | uncertain significance | not provided | no assertion criteria provided | clinical testing | ||
Genome Diagnostics Laboratory, |
RCV001699024 | SCV001927777 | uncertain significance | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV001699024 | SCV001974379 | uncertain significance | not provided | no assertion criteria provided | clinical testing |