ClinVar Miner

Submissions for variant NM_001174089.2(SLC4A11):c.2480T>C (p.Leu827Pro)

gnomAD frequency: 0.00005  dbSNP: rs121909394
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000595591 SCV000707632 likely pathogenic not provided 2017-04-12 criteria provided, single submitter clinical testing
Invitae RCV000595591 SCV001385596 pathogenic not provided 2023-09-20 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC4A11 function (PMID: 24916015, 29327391). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC4A11 protein function. ClinVar contains an entry for this variant (Variation ID: 1316). This missense change has been observed in individual(s) with Harboyan syndrome (PMID: 17220209, 27057589). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121909394, gnomAD 0.005%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 843 of the SLC4A11 protein (p.Leu843Pro).
Fulgent Genetics, Fulgent Genetics RCV002490290 SCV002786528 pathogenic Corneal dystrophy-perceptive deafness syndrome; Congenital hereditary endothelial dystrophy of cornea; Corneal dystrophy, Fuchs endothelial, 4 2022-01-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000001379 SCV003928601 pathogenic Corneal dystrophy-perceptive deafness syndrome 2023-04-12 criteria provided, single submitter clinical testing Variant summary: SLC4A11 c.2528T>C (p.Leu843Pro) results in a non-conservative amino acid change located in the transmembrane region 14 (TM14) (Badior_2016) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251080 control chromosomes (gnomAD). c.2528T>C has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Corneal Dystrophy And Perceptive Deafness (Desir_2007, Hand_2016). In addition, this variant was co-segregated with disease in one family (Hand_2016). These data indicate that the variant is very likely to be associated with disease. At least two functional studies reported this variant failed to reach the cell surface in transfected cells (Loganathan_2014, Alka_2018). Four ClinVar submitters (evaluation after 2014) cite this variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000001379 SCV000021529 pathogenic Corneal dystrophy-perceptive deafness syndrome 2007-05-01 no assertion criteria provided literature only
Natera, Inc. RCV000001379 SCV002090915 pathogenic Corneal dystrophy-perceptive deafness syndrome 2020-01-24 no assertion criteria provided clinical testing

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