ClinVar Miner

Submissions for variant NM_014252.4(SLC25A15):c.337G>A (p.Gly113Ser)

gnomAD frequency: 0.00003  dbSNP: rs199894905
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001113456 SCV001271229 uncertain significance Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV001113456 SCV001577929 pathogenic Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome 2024-01-19 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 113 of the SLC25A15 protein (p.Gly113Ser). This variant is present in population databases (rs199894905, gnomAD 0.01%). This missense change has been observed in individual(s) with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (PMID: 30187369, 30243302). 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: 883225). 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 SLC25A15 protein function. This variant disrupts the p.Gly113 amino acid residue in SLC25A15. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16601889, 19242930, 26589310, 30243302). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001570454 SCV001794749 likely pathogenic not provided 2022-12-09 criteria provided, single submitter clinical testing 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: 26147798, Mahmoud2019[In silico], 30187369, 30243302)
Ambry Genetics RCV002555095 SCV003760670 likely pathogenic Inborn genetic diseases 2021-10-29 criteria provided, single submitter clinical testing The c.337G>A (p.G113S) alteration is located in exon 4 (coding exon 3) of the SLC25A15 gene. This alteration results from a G to A substitution at nucleotide position 337, causing the glycine (G) at amino acid position 113 to be replaced by a serine (S). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (18/251448) total alleles studied. The highest observed frequency was 0.01% (15/113756) of European (non-Finnish) alleles. The p.G113S alteration has been reported as confirmed or presumably in trans with a second alteration in SLC25A15 in patients with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (Silfverberg, 2018; Wild, 2019). Another alteration at this position (p.G113C) has also been reported (reviewed in Martinelli, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Baylor Genetics RCV001113456 SCV004201672 pathogenic Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome 2023-10-12 criteria provided, single submitter clinical testing

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