ClinVar Miner

Submissions for variant NM_004519.4(KCNQ3):c.2123G>T (p.Ser708Ile)

gnomAD frequency: 0.00001  dbSNP: rs977989588
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000659109 SCV000780922 uncertain significance not provided 2018-01-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001481241 SCV001685579 likely benign Benign neonatal seizures 2024-09-16 criteria provided, single submitter clinical testing
GeneDx RCV000659109 SCV002003394 uncertain significance not provided 2020-02-05 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000659109 SCV001550526 uncertain significance not provided no assertion criteria provided clinical testing The KCNQ3 p.Ser588Ile variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs977989588) and in ClinVar (classified as likely benign by Invitae and as uncertain significance by CeGaT (Germany)). The variant was identified in control databases in 2 of 282774 chromosomes at a frequency of 0.000007073 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 2 of 129126 chromosomes (freq: 0.000015), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Ser588 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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