Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000035819 | SCV000059470 | uncertain significance | not specified | 2011-05-27 | criteria provided, single submitter | clinical testing | The Gln907Lys variant has not been reported in the literature but has been detec ted in 2/90 Hispanic cardiomyopathy probands tested by our laboratory. Because h ealthy control information is unavailable for this population we are unable to e xclude that this variant is common and therefore benign. In one of the families, the variant was present in 3 affected individuals, whcih is consistent with a p athogenic role. However, glutamine (Gln) at amino acid position 907 is conserved in mammals and chicken but not in evolutionary distant species (zebrafish fish carries a glycine), reducing the likelihood that the change is pathogenic. In ad dition, computational predictions are inconsistent. Three tools (AlignGVGD, SIF T, MAPP) predict that the variant is deleterious but their accuracy is unknown. In contrast, the variant was predicted to be benign using a novel tool, which wa s validated by our laboratory using a set of cardiomyopathy variants with well-e stablished clinical significance. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In summary, additional data (healthy c ontrol studies and familial segregation) are needed to determine the clinical si gnificance of this variant. |
| Invitae | RCV001852730 | SCV002218465 | uncertain significance | Hypertrophic cardiomyopathy | 2024-01-09 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 907 of the MYH7 protein (p.Gln907Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42928). 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 MYH7 protein function. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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. |