ClinVar Miner

Submissions for variant NM_017415.3(KLHL3):c.1019C>T (p.Ala340Val)

dbSNP: rs199469628
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001753490 SCV001986376 uncertain significance not provided 2019-01-09 criteria provided, single submitter clinical testing Identified in heterozygous state in a patient with hypoaldosteronism referred for genetic testing at GeneDx and in published literature in unrelated individuals with pseudohypoaldosteronism type II (Boyden et al., 2012; Glover et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Functional studies demonstrated that A340V shows binding to Cullin 3 and WNK1 that is similar to wild type KLHL3 protein (Ohta et al., 2013); This variant is associated with the following publications: (PMID: 22266938, 23387299, 24641320, 24266877)
Fulgent Genetics, Fulgent Genetics RCV002477256 SCV002778168 uncertain significance Pseudohypoaldosteronism type 2D 2022-02-08 criteria provided, single submitter clinical testing
Invitae RCV001753490 SCV004292860 uncertain significance not provided 2023-01-25 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 340 of the KLHL3 protein (p.Ala340Val). This variant is present in population databases (rs199469628, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant Gordon's syndrome (PMID: 22266938). ClinVar contains an entry for this variant (Variation ID: 100530). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect KLHL3 function (PMID: 23387299). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Richard Lifton Laboratory, Yale University School of Medicine RCV000128502 SCV000119152 pathogenic Pseudohypoaldosteronism type 2A no assertion criteria provided not provided Converted during submission to Pathogenic.

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