Submissions for variant NM_000342.4(SLC4A1):c.1766G>A (p.Arg589His)

dbSNP: rs121912744

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387018	SCV001587506	pathogenic	not provided	2022-09-27	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg589 amino acid residue in SLC4A1. Other variant(s) that disrupt this residue have been observed in individuals with SLC4A1-related conditions (PMID: 9312167, 29627839), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects SLC4A1 function (PMID: 9312167, 16420521). 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 SLC4A1 protein function. ClinVar contains an entry for this variant (Variation ID: 17763). This missense change has been observed in individual(s) with autosomal dominant familial renal tubular acidosis (PMID: 9312167, 29627839, 30230413). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 589 of the SLC4A1 protein (p.Arg589His).
Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi	RCV000019340	SCV002102797	pathogenic	Autosomal dominant distal renal tubular acidosis	2022-03-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002513120	SCV003550164	pathogenic	Inborn genetic diseases	2021-01-15	criteria provided, single submitter	clinical testing	The c.1766G>A (p.R589H) alteration is located in exon 14 (coding exon 13) of the SLC4A1 gene. This alteration results from a G to A substitution at nucleotide position 1766, causing the arginine (R) at amino acid position 589 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD), the SLC4A1 c.1766G>A alteration was not observed, with coverage at this position. This mutation has been identified in individuals with distal renal tubular acidosis, including one de novo case, and was shown to segregate with disease (Bruce, 1997; Karet, 1998; Bertocchio, 2020). HEK293 and MDCK cells expressing this mutation demonstrated reduced level of cell surface expression (Quilty, 2002; Cordat, 2006). Based on the available evidence, this alteration is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004549380	SCV004120615	pathogenic	SLC4A1-related disorder	2023-03-28	criteria provided, single submitter	clinical testing	The SLC4A1 c.1766G>A variant is predicted to result in the amino acid substitution p.Arg589His. This variant has been reported to be pathogenic for autosomal dominant distal renal tubular acidosis in several unrelated families (Jarolim et al. 1998. PubMed ID: 9497368; Shayakul et al. 2004. PubMed ID: 14736961; Bruce et al. 1997. PubMed ID: 9312167; Liu J et al 2018. PubMed ID: 30230413). Different changes at the same codon have also been reported to be pathogenic for autosomal dominant distal renal tubular acidosis (p.Arg589Ser in Karet et al.1998. PubMed ID: 9600966; p.Arg589Cys at Bruce et al. 1997. PubMed ID: 9312167). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000019340	SCV005091090	pathogenic	Autosomal dominant distal renal tubular acidosis	2024-03-13	criteria provided, single submitter	clinical testing	PS4, PM2, PP3, PM5, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 17763). This variant has been previously reported as causative (PMID:19565014).
Fulgent Genetics, Fulgent Genetics	RCV005007880	SCV005640048	pathogenic	BLOOD GROUP--SWANN SYSTEM; BLOOD GROUP--WALDNER TYPE; BLOOD GROUP--FROESE; BLOOD GROUP--WRIGHT ANTIGEN; Southeast Asian ovalocytosis; Hereditary spherocytosis type 4; BLOOD GROUP--DIEGO SYSTEM; Cryohydrocytosis; Autosomal dominant distal renal tubular acidosis; Renal tubular acidosis, distal, 4, with hemolytic anemia; Malaria, susceptibility to	2024-06-09	criteria provided, single submitter	clinical testing
OMIM	RCV000019340	SCV000039630	pathogenic	Autosomal dominant distal renal tubular acidosis	1998-05-26	no assertion criteria provided	literature only
Yale Center for Mendelian Genomics, Yale University	RCV001849273	SCV002106694	pathogenic	Distal renal tubular acidosis	2019-10-22	no assertion criteria provided	literature only
Genetic Services Laboratory, University of Chicago	RCV001387018	SCV003840060	pathogenic	not provided	2022-02-21	no assertion criteria provided	clinical testing	DNA sequence analysis of the SLC4A1 gene demonstrated a sequence change, c.1766G>A, in exon 14 that results in an amino acid change, p.Arg589His. This sequence change has not been described in population databases such as ExAC and gnomAD. The p.Arg589His change affects a highly conserved amino acid residue located in a domain of the SLC4A1 protein that is known to be functional. The p.Arg589His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Experimental studies have demonstrated that this sequence change impacts function of the SLC4A1 protein (PMID: 9312167, 164205210). This pathogenic sequence change has previously been described in multiple individuals with distal renal tubular acidosis (PMID: 29627839, 9497368, 30230413, 9312167). Additionally, other missense variants at this same position (p.Arg589Cys, p.Arg589Ser) have been reported individuals with SLC4A1-related disorders (PMID: 11149111, 30256676). Based on these collective evidences, this sequence change is classified as pathogenic.