ClinVar Miner

Submissions for variant NM_000342.4(SLC4A1):c.1199_1225del (p.Ala400_Ala408del)

dbSNP: rs769664228
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001377074 SCV001574307 pathogenic not provided 2023-12-21 criteria provided, single submitter clinical testing This variant, c.1199_1225del, results in the deletion of 9 amino acid(s) of the SLC4A1 protein (p.Ala400_Ala408del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs769664228, gnomAD 0.02%). This variant has been observed in individual(s) with autosomal dominant ovalocytosis and/or autosomal recessive distal renal tubular acidosis (PMID: 1722314, 1737855, 7919393, 7949112, 14618420, 19229254, 24652967, 28188436, 31672324, 31959358; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 17753). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SLC4A1 function (PMID: 7689982, 16107207). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV001377074 SCV001712909 pathogenic not provided 2019-10-10 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV001536118 SCV001752834 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 2022-01-27 criteria provided, single submitter clinical testing
3billion RCV001807735 SCV002058603 likely pathogenic Renal tubular acidosis, distal, 4, with hemolytic anemia 2022-01-03 criteria provided, single submitter clinical testing This inframe deletion in the non-repeat region can change the length of the protein and disrupt protein function (PM4_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000017753). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000046, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity Omics RCV001377074 SCV003817041 pathogenic not provided 2023-09-25 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000019329 SCV003921806 pathogenic Southeast Asian ovalocytosis criteria provided, single submitter clinical testing - In-frame insertion/deletion in a non-repetitive region that has moderate conservation. - Variant is present in gnomAD (v2) <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in many heterozygous individuals with SA type ovalocytosis, and is highly prevalent within South Asian populations (PMIDs: 30124986, 19229254, 7949112). Additionally, carriers of this variant have some resistance to all forms of malaria (PMID: 31364155, OMIM). It is highly likely to be lethal in homozygosity, where rare survivors demonstrate severe anaemia, hydrops and distal renal tubular acidosis (PMID: 24652967). - Strong phenotype match for this individual. Additional information: - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with SLC4A1-related disease. Spherocytosis type 4 (MIM#612653) is caused by variants with a loss of function mechanism. Cryohydrocytosis (MIM#185020), distal renal tubular acidosis (dRTA) (MIM#1179800), dRTA 4 with hemolytic anemia (MIM#611590) and SA type ovalocytosis (SAO) (MIM#166900) are caused by variants with either a loss of function, or dominant negative mechanism (PMID: 27058983). - This gene is associated with both recessive and dominant disease. Most reports for this gene are for dominant disease, however, individuals biallelic for variants causing SAO have a more severe phenotype (OMIM, PMID: 17557941). - This variant is homozygous. - Variant is located in the annotated anion exchange transporter domain (UniProt, DECIPHER). - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis).
Institute of Human Genetics, University of Leipzig Medical Center RCV001807735 SCV004027790 likely pathogenic Renal tubular acidosis, distal, 4, with hemolytic anemia 2023-05-19 criteria provided, single submitter clinical testing Criteria applied: PM5_STR,PM4,PM2_SUP
OMIM RCV000019329 SCV000039619 pathogenic Southeast Asian ovalocytosis 2009-03-01 no assertion criteria provided literature only
OMIM RCV000019330 SCV000039620 protective Malaria, cerebral, resistance to 2009-03-01 no assertion criteria provided literature only
Yale Center for Mendelian Genomics, Yale University RCV001849272 SCV002106696 pathogenic Distal renal tubular acidosis 2019-10-22 no assertion criteria provided literature only

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