Submissions for variant NM_014252.4(SLC25A15):c.380C>T (p.Thr127Met)

gnomAD frequency: 0.00010  dbSNP: rs201902280

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mayo Clinic Laboratories, Mayo Clinic	RCV000660372	SCV000782444	uncertain significance	Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome	2016-05-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000660372	SCV000894832	uncertain significance	Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000660372	SCV001271231	uncertain significance	Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome	2018-01-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000660372	SCV003269537	uncertain significance	Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome	2022-10-12	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 127 of the SLC25A15 protein (p.Thr127Met). This variant is present in population databases (rs201902280, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SLC25A15-related conditions. ClinVar contains an entry for this variant (Variation ID: 547845). 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. 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.
Ambry Genetics	RCV002530566	SCV003709710	uncertain significance	Inborn genetic diseases	2024-07-10	criteria provided, single submitter	clinical testing	The c.380C>T (p.T127M) alteration is located in exon 4 (coding exon 3) of the SLC25A15 gene. This alteration results from a C to T substitution at nucleotide position 380, causing the threonine (T) at amino acid position 127 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV004723046	SCV005333704	uncertain significance	not provided	2024-02-15	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; Missense variants in this gene are often considered pathogenic (HGMD); Has not been previously published as pathogenic or benign to our knowledge