ClinVar Miner

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

dbSNP: rs121912744
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae 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 RCV003398546 SCV004120615 pathogenic SLC4A1-related condition 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.
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.

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