Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000034356 | SCV000963898 | uncertain significance | EAST syndrome | 2019-08-23 | criteria provided, single submitter | clinical testing | 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. This variant has been reported to affect KCNJ10 protein function (PMID:20651251). This variant has been observed in an individual affected with EAST syndrome (PMID: 20651251). ClinVar contains an entry for this variant (Variation ID: 41471). This variant is present in population databases (rs397514673, ExAC 0.01%). This sequence change replaces arginine with glutamine at codon 175 of the KCNJ10 protein (p.Arg175Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. |
| Genetic Services Laboratory, |
RCV001818209 | SCV002064381 | likely pathogenic | not provided | 2019-07-16 | criteria provided, single submitter | clinical testing | This sequence change, c.524G>A, in exon 2 results in an amino acid change, p.Arg175Gln. This has been previously described in the homozygous state a patient with ataxia, infantile onset epilepsy, sensorineural hearing loss and biochemical studies consistent with hypomagnesemia and hypokalemia (Reichold et al., 2010). In vitro functional expression assays showed that this variant severely impaired Kir4.1 channel activity through reducing channel open probability and PIP2 affinity which is important for channel activity. These results were suggestive of loss of channel function (Reichold et al., 2010). This particular sequence change has been described in the gnomAD database in two individuals in the heterozygous state which corresponds to a population frequency of 0.00092% (rs397514673). The p.Arg175Gln change affects a highly conserved amino acid residue located in a domain of the KCNJ10 protein that is known to be functional. The p.Arg175Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). These evidences indicate that this sequence change is likely pathogenic. |
| Ambry Genetics | RCV002336110 | SCV002645399 | likely pathogenic | Inborn genetic diseases | 2017-08-25 | criteria provided, single submitter | clinical testing | The p.R175Q variant (also known as c.524G>A), located in coding exon 1 of the KCNJ10 gene, results from a G to A substitution at nucleotide position 524. The arginine at codon 175 is replaced by glutamine, an amino acid with highly similar properties. In one study, this variant was detected as homozygous in an individual with a diagnosis of EAST syndrome who had epilepsy, ataxia, sensorineural deafness, hypomagnesemia, and hypokalemia. In addition, authors of this study performed functional studies showing that this alteration causes a marked impairment of channel function, a decrease in current, and a remarkable shift of pH sensitivity (Reichold M et al. Proc. Natl. Acad. Sci. U.S.A., 2010 Aug;107:14490-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| OMIM | RCV000034356 | SCV000058338 | pathogenic | EAST syndrome | 2010-08-10 | no assertion criteria provided | literature only |