Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001341338 | SCV001535207 | uncertain significance | Hypertrophic cardiomyopathy 14 | 2024-04-27 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1820 of the MYH6 protein (p.Arg1820Gln). This variant is present in population databases (rs371222772, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of MYH6-related conditions (PMID: 31534214, 36303204). ClinVar contains an entry for this variant (Variation ID: 1038078). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH6 protein function. 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. |
| Fulgent Genetics, |
RCV002486376 | SCV002787884 | uncertain significance | Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to | 2021-07-28 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV004988563 | SCV005453706 | uncertain significance | Cardiovascular phenotype | 2024-06-25 | criteria provided, single submitter | clinical testing | The p.R1820Q variant (also known as c.5459G>A), located in coding exon 34 of the MYH6 gene, results from a G to A substitution at nucleotide position 5459. The arginine at codon 1820 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in individuals from sudden death cohorts who had additional variants in other cardiac related genes, including an individual with hypertrophic cardiomyopathy and a frameshift variant in MYBPC3 (Subbotina E et al. Forensic Sci. Int., 2018 Dec;293:37-46; Lahrouchi N et al. Eur. J. Hum. Genet., 2020 Jan;28:17-22). This variant has also been reported in a pediatric cardiomyopathy cohort and arrhythmia cohort (Ware SM et al. Am J Hum Genet, 2022 Feb;109:282-298; Chen J et al. Orphanet J Rare Dis, 2022 Oct;17:394). This amino acid position is well conserved in available vertebrate species; however, glutamine is the reference amino acid in other 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. |
| Clinical Genomics Laboratory, |
RCV005232275 | SCV005873519 | uncertain significance | Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14 | 2022-03-04 | criteria provided, single submitter | clinical testing | The p.Arg1820Gln variant in the MYH6 gene has been previously reported in an individual with hypertrophic cardiomyopathy who underwent postmortem genetic testing. However, a truncating, likely pathogenic variant in MYBPC3 (p.S18Tfs*31) was also identified in this individual (Lahrouchi et al., 2020). This variant has been identified in 8/30,614 South Asian chromosomes (15/282,834 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, it has not been observed at a frequency high enough to rule out pathogenicity. The arginine at position 1820 is moderately evolutionarily conserved and a glutamine is seen at this position is several vertebrate species. Computational tools predict that the p.Arg1820Gln variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Arg1820Gln variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PP3] |