rs80338794
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 15P and 1B. PM1PM2PM5PP3PP5_Very_StrongBP4
The NM_012434.5(SLC17A5):โc.115C>Tโ(p.Arg39Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000364 in 1,614,004 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (โ โ ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R39H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_012434.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC17A5 | NM_012434.5 | c.115C>T | p.Arg39Cys | missense_variant | 2/11 | ENST00000355773.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC17A5 | ENST00000355773.6 | c.115C>T | p.Arg39Cys | missense_variant | 2/11 | 1 | NM_012434.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000454 AC: 69AN: 152148Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000827 AC: 208AN: 251452Hom.: 0 AF XY: 0.000809 AC XY: 110AN XY: 135914
GnomAD4 exome AF: 0.000355 AC: 519AN: 1461738Hom.: 1 Cov.: 31 AF XY: 0.000347 AC XY: 252AN XY: 727172
GnomAD4 genome ? AF: 0.000453 AC: 69AN: 152266Hom.: 0 Cov.: 33 AF XY: 0.000658 AC XY: 49AN XY: 74454
ClinVar
Submissions by phenotype
Salla disease Pathogenic:10
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 14, 2005 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 06, 2018 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Jun 04, 2020 | - - |
Pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | 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. - |
Pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 19, 2019 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:8
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 14, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 21, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 16, 2021 | 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tรผbingen | Feb 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2022 | 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) - |
Sialic acid storage disease, severe infantile type Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | 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. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | research | Bruce Lefroy Centre, Murdoch Childrens Research Institute | - | - - |
Sialic acid storage disease, severe infantile type;C1096903:Salla disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 13, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at