ClinVar Miner

Submissions for variant NM_000276.4(OCRL):c.40A>G (p.Thr14Ala)

gnomAD frequency: 0.00003  dbSNP: rs371099243
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001817561 SCV002068856 uncertain significance not specified 2018-04-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001817561 SCV002570564 uncertain significance not specified 2022-07-08 criteria provided, single submitter clinical testing Variant summary: OCRL c.40A>G (p.Thr14Ala) results in a non-conservative amino acid change located in the OCRL1, PH domain (IPR037787) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing, however, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 204391 control chromosomes, including 1 hemizygote (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.40A>G has been reported in the literature in one individual with idiopathic infantile hypercalcemia (Lenherr-Taube_2021). This report does not provide unequivocal conclusions about association of the variant with Dent Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV002482356 SCV002792264 uncertain significance Dent disease type 2; Lowe syndrome 2022-05-25 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002542541 SCV003270090 uncertain significance Lowe syndrome 2022-06-11 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 14 of the OCRL protein (p.Thr14Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with OCRL-related conditions. ClinVar contains an entry for this variant (Variation ID: 1336606). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.

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