Submissions for variant NM_014252.4(SLC25A15):c.182G>A (p.Arg61His)

gnomAD frequency: 0.00292  dbSNP: rs34615430

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726011	SCV000239188	uncertain significance	not provided	2018-04-03	criteria provided, single submitter	clinical testing	The R61H variant in the SLC25A15 gene has been reported as a rare variant identified in 12 patients with multiple sclerosis, but was also observed in 10 healthy controls (Traboulsee et al., 2017). The R61H variant is observed in 577/126660 (0.45%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The R61H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R61H as a variant of uncertain significance.
Eurofins Ntd Llc (ga)	RCV000726011	SCV000341202	uncertain significance	not provided	2016-04-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000401214	SCV000384410	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV000401214	SCV000631855	likely benign	Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000726011	SCV001149010	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	SLC25A15: BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000401214	SCV001158859	uncertain significance	Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome	2023-09-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003907650	SCV004723020	likely benign	SLC25A15-related disorder	2022-02-16	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001251645	SCV001427385	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000726011	SCV001548952	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SLC25A15 p.Arg61His variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs34615430), ClinVar (classified as a VUS by GeneDx, EGL Genetics and Illumina and as likely benign by Invitae for hyperornithinemia-hyperammonemia-homocitrullinemia syndrome) and LOVD 3.0 (reported as likely benign). The variant was identified in control databases in 663 of 282814 chromosomes at a frequency of 0.002344 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 582 of 129132 chromosomes (freq: 0.004507), Other in 18 of 7228 chromosomes (freq: 0.00249), African in 23 of 24958 chromosomes (freq: 0.000922), Latino in 30 of 35438 chromosomes (freq: 0.000847) and European (Finnish) in 10 of 25122 chromosomes (freq: 0.000398); it was not observed in the Ashkenazi Jewish, East Asian and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg61 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.