Submissions for variant NM_012434.5(SLC17A5):c.115C>T (p.Arg39Cys)

gnomAD frequency: 0.00049  dbSNP: rs80338794

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000414141	SCV000227418	pathogenic	not provided	2014-10-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000414141	SCV000490800	pathogenic	not provided	2022-10-04	criteria provided, single submitter	clinical testing	Published functional studies have shown R39C reduces sialic acid transport across the lysosomal membrane, abolishing aspartate and glutamate transport ability and decreasing H+/sialic acid co-transport activity (Morin et al., 2004; Miyaji et al., 2011).; This variant is associated with the following publications: (PMID: 12794688, 23227378, 18695252, 21781115, 15516337, 12359136, 22778404, 10581036, 29140481, 33862140, 31589614, 10947946, 15510212)
SIB Swiss Institute of Bioinformatics	RCV000005967	SCV000803591	pathogenic	Salla disease	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Pathogenic, for Salla disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:10947946). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:10581036). PS3 => Well-established functional studies show a deleterious effect (PMID:21781115). PM2 => Present in Exome Aggregation Consortium with allele frequency compatible with carrier frequency. PS4-Supporting => Frequent mutation observed in multiple patients.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000005967	SCV000832695	pathogenic	Salla disease	2024-07-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 39 of the SLC17A5 protein (p.Arg39Cys). This variant is present in population databases (rs80338794, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with Salla disease (PMID: 10581036, 10947946, 12794688). ClinVar contains an entry for this variant (Variation ID: 5615). 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%. Experimental studies have shown that this missense change affects SLC17A5 function (PMID: 12359136, 15510212, 15516337, 18695252, 21781115). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763563	SCV000894394	pathogenic	Sialic acid storage disease, severe infantile type; Salla disease	2024-03-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000005967	SCV000918214	pathogenic	Salla disease	2018-08-06	criteria provided, single submitter	clinical testing	Variant summary: SLC17A5 c.115C>T (p.Arg39Cys) results in a non-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 0.00081 in 277222 control chromosomes (gnomAD and publications). The variant, c.115C>T, has been reported as a common disease variant and a Finnish founder mutation in individuals affected with Sialic Acid Storage Disorder (Aula_2000, Verheijen_1999). These reports suggest individuals homozygous for the variant have milder phenotype compared to those who carry a different pathogenic mutation in trans. Functionally, the variant is reported to lead to a complete loss of aspartate and glutamate transport activity, while retaining some H+/sialic acid co-transport activity (Miyaji_2011, Morin_2004). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000005967	SCV001193930	pathogenic	Salla disease	2019-12-19	criteria provided, single submitter	clinical testing	NM_012434.4(SLC17A5):c.115C>T(R39C) is classified as pathogenic in the context of Salla disease. Sources cited for classification include the following: PMID 11992753, 12359136, 15510212 and 21781115. Classification of NM_012434.4(SLC17A5):c.115C>T(R39C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000414141	SCV001250035	pathogenic	not provided	2018-02-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001095363	SCV001368661	pathogenic	Sialic acid storage disease, severe infantile type	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM3,PP3. This variant was detected in homozygous state.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000414141	SCV001480120	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Genomic Medicine Lab, University of California San Francisco	RCV000005967	SCV001572960	pathogenic	Salla disease	2020-06-04	criteria provided, single submitter	clinical testing
Bruce Lefroy Centre, Murdoch Childrens Research Institute	RCV001095363	SCV001879319	pathogenic	Sialic acid storage disease, severe infantile type		criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000414141	SCV002020634	pathogenic	not provided	2023-06-21	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000005967	SCV002027583	pathogenic	Salla disease	2021-09-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000414141	SCV002064394	pathogenic	not provided	2021-06-16	criteria provided, single submitter	clinical testing	DNA sequence analysis of the SLC17A5 gene demonstrated a sequence change, c.115C>T, in exon 2 that results in an amino acid change, p.Arg39Cys. This sequence change has been described in the gnomAD database in the Finnish European subpopulation with a low frequency of 0.593% (dbSNP rs80338794). This sequence change has been previously described in the homozygous and compound heterozygous states in several individuals with lysosomal free sialic acid storage diseases (PMIDs:10947946, 10581036), and is a founder pathogenic variant in the Finnish population. The p.Arg39Cys change affects a highly conserved amino acid residue located in a domain of the SLC17A5 protein that is known to be functional. The p.Arg39Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies show p.Arg39Cys disrupts the SLC17A5 transporter activity (PMID:21781115). Collectively this evidence indicates p.Arg39Cys is pathogenic.
Baylor Genetics	RCV000005967	SCV004201204	pathogenic	Salla disease	2024-03-25	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000414141	SCV005198252	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
OMIM	RCV000005967	SCV000026149	pathogenic	Salla disease	2005-01-14	no assertion criteria provided	literature only
GeneReviews	RCV001095363	SCV000041226	not provided	Sialic acid storage disease, severe infantile type		no assertion provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000005967	SCV001142364	pathogenic	Salla disease	2020-01-06	no assertion criteria provided	curation	NM_012434.4:c.115C>T in the SLC17A5 gene has an allele frequency of 0.006 in European (Finnish) subpopulation in the gnomAD database. Frans W. et al. found a homozygous SLC17A5 mutation (R39C) in five Finnish patients with Salla disease (PMID: 10581036). This variant has been reported as homozygous or compound heterozygous in many individuals affected with Salla disease and it is a well known founder in the Finnish population (PMID: 10947946; 12794688). Experimental studies have shown that this missense change affects protein trafficking to the lysosomes, abolishes aspartate and glutamate transport ability and causes a significant reduction of sialic acid cotransport activity (PMID: 21781115). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PS3; PM3_Strong; PP4.
Natera, Inc.	RCV000005967	SCV001453518	pathogenic	Salla disease	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000414141	SCV001742960	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000414141	SCV001973812	pathogenic	not provided		no assertion criteria provided	clinical testing