Submissions for variant NM_000342.4(SLC4A1):c.1468C>T (p.Arg490Cys)

gnomAD frequency: 0.00001  dbSNP: rs1398477044

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mayo Clinic Laboratories, Mayo Clinic	RCV001507382	SCV001712908	pathogenic	not provided	2021-02-08	criteria provided, single submitter	clinical testing	PS3, PS4, PP1_moderate, PP3
GeneDx	RCV001507382	SCV001794957	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate abnormal protein trafficking and a damaging dominant negative effect (Dhermy et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29572776, 9233560, 10766130)
Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University	RCV002290998	SCV002500016	likely pathogenic	Hereditary spherocytosis type 4	2022-03-01	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV001507382	SCV003812794	pathogenic	not provided	2023-07-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001507382	SCV004298226	likely pathogenic	not provided	2024-02-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 490 of the SLC4A1 protein (p.Arg490Cys). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individual(s) with hereditary spherocytosis (PMID: 9233560, 29572776, 36203343). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1162816). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC4A1 function (PMID: 9565662, 10766130). This variant disrupts the p.Arg490 amino acid residue in SLC4A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10580570, 31126250). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001507382	SCV005879421	pathogenic	not provided	2024-08-15	criteria provided, single submitter	clinical testing	The SLC4A1 c.1468C>T; p.Arg490Cys variant (rs1398477044, ClinVar Variation ID: 1162816), also known as Band 3 Bicetre, is reported as both an inherited and de novo variant in several individuals with hereditary spherocytosis or hemolytic anemia from multiple different families (Dhermy 1997, Wang 2018, Wang 2023). Both in vitro and in vivo functional analyses with mutant protein demonstrate mislocalization, altered protein folding and premature protein degradation leading to altered transport activity (Dhermy 1999). The mutant peptide also disrupts the localization of normal Band 3 protein through a dominant negative effect (Karbach 1998). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, another variant at this codon (c.1469G>A; p.Arg490His) has been reported in individuals with hereditary spherocytosis (Lima 1999, Shen 2019, Svidnicki 2020, Van Zwieten 2013, Vives-Corrons 2021). Computational analyses predict that this variant is deleterious (REVEL: 0.848). Based on available information, this variant is considered to be pathogenic. References: Dhermy D et al. The red blood cell band 3 variant (band 3Biceetrel:R490C) associated with dominant hereditary spherocytosis causes defective membrane targeting of the molecule and a dominant negative effect. Mol Membr Biol. 1999 Oct-Nov. PMID: 10766130. Dhermy D et al. Heterogenous band 3 deficiency in hereditary spherocytosis related to different band 3 gene defects. Br J Haematol. 1997 Jul. PMID: 9233560. Karbach D et al. Effect of site-directed mutagenesis of the arginine residues 509 and 748 on mouse band 3 protein-mediated anion transport. Biochim Biophys Acta. 1998 Apr 22. PMID: 9565662. Lima PR et al. Arginine 490 is a hot spot for mutation in the band 3 gene in hereditary spherocytosis. Eur J Haematol. 1999 Nov. PMID: 10580570. Shen H et al. Two different pathogenic gene mutations coexisted in the same hereditary spherocytosis family manifested with heterogeneous phenotypes. BMC Med Genet. 2019 May 24. PMID: 31126250. Svidnicki M et al. Targeted next-generation sequencing identified novel mutations associated with hereditary anemias in Brazil. Ann Hematol. 2020 May. PMID: 32266426. Van Zwieten R et al. Hereditary spherocytosis due to band 3 deficiency: 15 novel mutations in SLC4A1. Am J Hematol. 2013 Feb. PMID: 23255290. Vives-Corrons JL et al. Characterization of hereditary red blood cell membranopathies using combined targeted next-generation sequencing and osmotic gradient ektacytometry. Int J Hematol. 2021 Feb. PMID: 33074480. Wang R et al. Exome sequencing confirms molecular diagnoses in 38 Chinese families with hereditary spherocytosis. Sci China Life Sci. 2018 Aug. PMID: 29572776. Wang WJ et al. Identification of variants in 94 Chinese patients with hereditary spherocytosis by next-generation sequencing. Clin Genet. 2023 Jan. PMID: 36203343.
PreventionGenetics, part of Exact Sciences	RCV004728747	SCV005337685	pathogenic	SLC4A1-related disorder	2024-07-22	no assertion criteria provided	clinical testing	The SLC4A1 c.1468C>T variant is predicted to result in the amino acid substitution p.Arg490Cys. This variant was reported in at least three kindreds and segregated with autosomal dominant hereditary spherocytosis (Dhermy et al 1997. PubMed ID: 9233560; Wang WJ et al 2022. PubMed ID: 36203343). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-42334876-G-A). This variant is interpreted as pathogenic.