ClinVar Miner

Submissions for variant NM_014252.4(SLC25A15):c.538G>A (p.Glu180Lys)

gnomAD frequency: 0.00002  dbSNP: rs104894424
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000514789 SCV000609719 pathogenic not provided 2017-04-20 criteria provided, single submitter clinical testing
Invitae RCV000006359 SCV001589952 pathogenic Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome 2023-11-06 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 180 of the SLC25A15 protein (p.Glu180Lys). This variant is present in population databases (rs104894424, gnomAD 0.007%). This missense change has been observed in individual(s) with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (PMID: 10369256; 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: 5993). 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 SLC25A15 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC25A15 function (PMID: 10369256, 26589310). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000006359 SCV004099567 likely pathogenic Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome 2023-09-06 criteria provided, single submitter clinical testing Variant summary: SLC25A15 c.538G>A (p.Glu180Lys) results in a conservative amino acid change in 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 8e-06 in 251488 control chromosomes. c.538G>A has been reported in trans along with a full/partial SLC25A15 deletion in at-least one individual affected with Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome (example, Camacho_1999). This variant has also been reported in an individual undertaking a genetic carrier screening (Capalbo_2019). At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in abolishment of the rescuing ability of SLC25A15 in vitro and in vivo (Camacho_1999, Doimo_2015). The following publications have been ascertained in the context of this evaluation (PMID: 10369256, 31589614, 26589310). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (both pathogenic). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000006359 SCV004201670 likely pathogenic Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome 2023-10-18 criteria provided, single submitter clinical testing
OMIM RCV000006359 SCV000026541 pathogenic Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome 1999-06-01 no assertion criteria provided literature only

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