Submissions for variant NM_017415.3(KLHL3):c.1583G>A (p.Arg528His)

dbSNP: rs199469636

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Fulgent Genetics, Fulgent Genetics	RCV000023475	SCV002776832	pathogenic	Pseudohypoaldosteronism type 2D	2024-05-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513190	SCV003439203	pathogenic	not provided	2022-09-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg528 amino acid residue in KLHL3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22266938). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 KLHL3 protein function. ClinVar contains an entry for this variant (Variation ID: 30518). This missense change has been observed in individuals with autosomal dominant pseudohypoaldosteronism type 2 (PMID: 22266938, 25925082). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 528 of the KLHL3 protein (p.Arg528His).
GeneDx	RCV002513190	SCV005421336	pathogenic	not provided	2024-06-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Arg496His; This variant is associated with the following publications: (PMID: 22406640, 24641320, 26607111, 23962426, 23453970, 23387299, 28743496, 25831548, 33682442, 28052936, 32203225, 36964972, 36028759, 25925082, 22266938, 27639857, 24821705)
OMIM	RCV000023475	SCV000044766	pathogenic	Pseudohypoaldosteronism type 2D	2014-10-01	no assertion criteria provided	literature only
Richard Lifton Laboratory, Yale University School of Medicine	RCV000128519	SCV000119169	pathogenic	Pseudohypoaldosteronism type 2A		no assertion criteria provided	not provided	Converted during submission to Pathogenic.