Submissions for variant NM_000342.4(SLC4A1):c.2278C>T (p.Arg760Trp)

dbSNP: rs373916826

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000989925	SCV001140659	pathogenic	Hereditary spherocytosis type 4	2019-05-28	criteria provided, single submitter	clinical testing
Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University	RCV000989925	SCV002500013	pathogenic	Hereditary spherocytosis type 4	2022-03-01	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002227236	SCV002506262	likely pathogenic	not provided	2022-02-24	criteria provided, single submitter	clinical testing
GeneDx	RCV002227236	SCV002571246	likely pathogenic	not provided	2022-03-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate defective cellular trafficking from the endoplasmic reticulum to the plasma membrane and non-native structures that may be misfolded (Quilty and Reithmeier, 2000); 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; This variant is associated with the following publications: (PMID: 7530501, 18304844, 32884076, 11208088, 32266426, 27292444, 19565014, 31122244)
Mayo Clinic Laboratories, Mayo Clinic	RCV002227236	SCV002573762	pathogenic	not provided	2021-11-08	criteria provided, single submitter	clinical testing	PP3, PM2, PS3, PS4
Labcorp Genetics (formerly Invitae), Labcorp	RCV002227236	SCV003441979	uncertain significance	not provided	2024-03-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 760 of the SLC4A1 protein (p.Arg760Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary spherocytosis (PMID: 7530501, 9012689, 10745622, 31122244, 32266426, 34093240, 36203343). ClinVar contains an entry for this variant (Variation ID: 803425). 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: 11208088). 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.
Revvity Omics, Revvity	RCV002227236	SCV003819165	pathogenic	not provided	2023-12-14	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000989925	SCV005417754	likely pathogenic	Hereditary spherocytosis type 4		criteria provided, single submitter	clinical testing	PM2_Supporting+PS3_Moderate+PM5_Supporting+PS4_Supporting+PP4
PreventionGenetics, part of Exact Sciences	RCV004740527	SCV005360707	pathogenic	SLC4A1-related disorder	2024-09-27	no assertion criteria provided	clinical testing	The SLC4A1 c.2278C>T variant is predicted to result in the amino acid substitution p.Arg760Trp. This variant has been reported in multiple unrelated individuals with spherocytosis (Jarolim et al. 1995. PubMed ID: 7530501; Choi et al. 2019. PubMed ID: 31122244; Svidnicki et al. 2020. PubMed ID: 32266426; Wang et al. 2023. PubMed ID: 36202243). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.