ClinVar Miner

Submissions for variant NM_002250.3(KCNN4):c.1055G>A (p.Arg352His)

dbSNP: rs774455945
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000239166 SCV000297117 pathogenic not provided 2015-10-30 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000239166 SCV001501739 pathogenic not provided 2020-10-01 criteria provided, single submitter clinical testing
GeneDx RCV000239166 SCV001784727 pathogenic not provided 2020-08-18 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect; Xenopus and transfected cells showed that the potassium channel exhibits a higher activity and a higher calcium sensitivity compared with the wild-type channel (Rapetti-Mauss et al., 2015); This variant is associated with the following publications: (PMID: 32641076, 30577886, 26148990, 26198474, 26178367, 28496185, 27443288)
Revvity Omics, Revvity RCV000412510 SCV002023216 pathogenic Dehydrated hereditary stomatocytosis 2 2021-10-13 criteria provided, single submitter clinical testing
3billion RCV000412510 SCV002058976 pathogenic Dehydrated hereditary stomatocytosis 2 2022-01-03 criteria provided, single submitter clinical testing Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:26148990, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.889, PP3_P). A missense variant is a common mechanism associated with Dehydrated hereditary stomatocytosis 2 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000252601, PMID:26148990, PS1_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center RCV000412510 SCV002581315 pathogenic Dehydrated hereditary stomatocytosis 2 2022-06-20 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000239166 SCV004242966 pathogenic not provided 2024-02-06 criteria provided, single submitter clinical testing
Invitae RCV000239166 SCV004298406 pathogenic not provided 2023-10-10 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 352 of the KCNN4 protein (p.Arg352His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with xerocytosis (PMID: 26148990, 26178367, 28496185). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 252601). 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 not expected to disrupt KCNN4 protein function. Experimental studies have shown that this missense change affects KCNN4 function (PMID: 26148990). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000412510 SCV000490257 pathogenic Dehydrated hereditary stomatocytosis 2 2015-12-11 no assertion criteria provided literature only

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