Submissions for variant NM_012434.5(SLC17A5):c.116G>A (p.Arg39His)

gnomAD frequency: 0.00001  dbSNP: rs769235753

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000496107	SCV000796029	likely pathogenic	Salla disease	2017-11-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001332964	SCV001525425	pathogenic	Sialic acid storage disease, severe infantile type	2019-11-04	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001548541	SCV001768469	likely pathogenic	not provided	2020-06-30	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 31130284, 27848944, 29472023)
Genome-Nilou Lab	RCV000496107	SCV002027582	likely pathogenic	Salla disease	2021-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496107	SCV003439472	likely pathogenic	Salla disease	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 39 of the SLC17A5 protein (p.Arg39His). This variant is present in population databases (rs769235753, gnomAD 0.006%). This missense change has been observed in individual(s) with SLC17A5-related conditions (PMID: 27848944, 31130284, 34979677, 35322241). ClinVar contains an entry for this variant (Variation ID: 431079). 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 SLC17A5 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg39 amino acid residue in SLC17A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10581036, 10947946, 12794688, 15510212, 15516337, 18695252, 21781115). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV000496107	SCV004201219	pathogenic	Salla disease	2024-03-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000496107	SCV004804960	likely pathogenic	Salla disease	2024-03-17	criteria provided, single submitter	research
Neuberg Centre For Genomic Medicine, NCGM	RCV001332964	SCV005382287	pathogenic	Sialic acid storage disease, severe infantile type	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense c.116G>A(p.Arg39His) variant in SLC17A5 gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with sialic acid storage disorders (Hu et al., 2023). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic / Likely Pathogenic (multiple submitters). The amino acid Arg at position 39 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg39His in SLC17A5 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - Probably damaging, SIFT - Damaging, and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. This variant disrupts the p.Arg39 amino acid residue in SLC17A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (Miyaji et al., 2011). For these reasons, this variant has been classified as Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000496107	SCV000586694	likely pathogenic	Salla disease	2016-10-13	no assertion criteria provided	clinical testing	This variant is not present in the 1000 Genomes database and has a minor allele frequency of less than 0.001% in the ExAC database. This variant is predicted to be damaging by SIFT, LRT, PolyPhen and Mutation Taster.
Genomics England Pilot Project, Genomics England	RCV001332964	SCV001760186	likely pathogenic	Sialic acid storage disease, severe infantile type		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000496107	SCV002076737	likely pathogenic	Salla disease	2020-03-25	no assertion criteria provided	clinical testing