Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000007889 | SCV001215694 | pathogenic | EAST syndrome | 2023-06-21 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) (PMID: 19289823, 23924083). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7463). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects KCNJ10 function (PMID: 20651251, 20678478, 20807765, 21088294). This sequence change creates a premature translational stop signal (p.Arg199*) in the KCNJ10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 181 amino acid(s) of the KCNJ10 protein. |
| Fulgent Genetics, |
RCV002496303 | SCV002813922 | pathogenic | Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome; EAST syndrome | 2022-01-04 | criteria provided, single submitter | clinical testing | |
| Broad Center for Mendelian Genomics, |
RCV000007889 | SCV003761261 | likely pathogenic | EAST syndrome | 2023-01-25 | criteria provided, single submitter | curation | The homozygous p.Arg199Ter variant in KCNJ10 was identified by our study in one individual with EAST syndrome. The p.Arg199Ter variant in KCNJ10 has been reported in one individual with EAST syndrome (PMID: 19289823). This individual was a compound heterozygote who carried a likely pathogenic variant in trans (ClinVar Variation ID: 7462), which increases the likelihood that the p.Arg199Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 7463) and has been interpreted as pathogenic by Invitae and OMIM. This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg199Ter variant may impact protein function (PMID: 20651251). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 199. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the KCNJ10 gene is strongly associated to autosomal recessive EAST syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive EAST syndrome. ACMG/AMP Criteria applied: PVS1_Moderate, PM2_Supporting, PS3_Supporting, PM3 (Richards 2015). |
| Gene |
RCV003128569 | SCV003805551 | pathogenic | not provided | 2022-08-23 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate that the variant causes loss of protein function as well as lack of cell surface protein expression (Tang et al., 2010; Reichold et al., 2010); Nonsense variant predicted to result in protein truncation as the last 181 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20807765, 21088294, 33996354, 34638578, 21849804, 26961251, 24480364, 28835827, 27129733, 22809040, 23922547, 27500072, 28520217, 30952461, 29722316, 20651251, 26147798, 29358904, 23924083, 20678478, 29722015, 19289823) |
| OMIM | RCV000007889 | SCV000028094 | pathogenic | EAST syndrome | 2010-08-10 | no assertion criteria provided | literature only |