ClinVar Miner

Submissions for variant NM_004700.4(KCNQ4):c.686C>T (p.Ser229Leu)

gnomAD frequency: 0.00002  dbSNP: rs1016512710
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001755050 SCV001995870 uncertain significance not provided 2019-09-18 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002540447 SCV003711079 uncertain significance Inborn genetic diseases 2021-07-20 criteria provided, single submitter clinical testing The c.686C>T (p.S229L) alteration is located in exon 4 (coding exon 4) of the KCNQ4 gene. This alteration results from a C to T substitution at nucleotide position 686, causing the serine (S) at amino acid position 229 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab RCV003446905 SCV004173175 uncertain significance Autosomal dominant nonsyndromic hearing loss 2A 2023-04-11 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001755050 SCV005728375 uncertain significance not provided 2024-05-06 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 229 of the KCNQ4 protein (p.Ser229Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with KCNQ4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1312296). 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) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ4 protein function with a positive predictive value of 95%. 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.

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