VCV000005615.66 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(23)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 5615 Accession: VCV000005615.66

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6q13 6: 73644583 (GRCh38) [ NCBI UCSC ] 6: 74354306 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 20, 2024	Mar 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_012434.5:c.115C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_036566.1:p.Arg39Cys	missense
NC_000006.12:g.73644583G>A
NC_000006.11:g.74354306G>A
NG_008272.1:g.14432C>T
	Q9NRA2:p.Arg39Cys

... more HGVS ... less HGVS

Protein change

R39C

Other names

NM_012434.4(SLC17A5):c.115C>T(p.Arg39Cys)

Canonical SPDI

NC_000006.12:73644582:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00040 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00018

1000 Genomes Project 30x 0.00031

1000 Genomes Project 0.00040

The Genome Aggregation Database (gnomAD) 0.00049

Exome Aggregation Consortium (ExAC) 0.00078

The Genome Aggregation Database (gnomAD), exomes 0.00083

Links

ClinGen: CA340439 UniProtKB: Q9NRA2#VAR_018684 OMIM: 604322.0001 dbSNP: rs80338794 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SLC17A5		-	-	GRCh38 GRCh37	566	663

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Salla disease	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Mar 25, 2024	RCV000005967.26
Sialic acid storage disease, severe infantile type	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 1, 2016	RCV001095363.7
not provided	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Jun 21, 2023	RCV000414141.42
Salla disease Sialic acid storage disease, severe infantile type	Pathogenic (1)	criteria provided, single submitter	Apr 13, 2022	RCV000763563.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 14, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000227418.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SLC17A5 Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Aug 06, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Salla disease Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000918214.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (4) PubMed: 10947946‚ 15510212‚ 10581036‚ 21781115 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 19, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Salla disease Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193930.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (4) PubMed: 11992753‚ 12359136‚ 15510212‚ 21781115 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Sialic acid storage disease, severe infantile type Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368661.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: 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.
Pathogenic (Feb 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001480120.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021	Clinical Features: Hypertelorism (present) , Bilateral talipes equinovarus (present) , Talipes (present) , Hypoplasia of the corpus callosum (present) , Drooling (present) , Leukoencephalopathy (present) , Axial … (more) Hypertelorism (present) , Bilateral talipes equinovarus (present) , Talipes (present) , Hypoplasia of the corpus callosum (present) , Drooling (present) , Leukoencephalopathy (present) , Axial hypotonia (present) , Infantile muscular hypotonia (present) , Oral motor hypotonia (present) , Movement disorder (present) (less) Sex: male
Pathogenic (Jun 04, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Salla disease (Autosomal recessive inheritance) Affected status: yes Allele origin: paternal	Genomic Medicine Lab, University of California San Francisco Study: CSER-P3EGS Accession: SCV001572960.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Sex: male
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Sialic acid storage disease, severe infantile type (Autosomal recessive inheritance) Affected status: yes Allele origin: paternal	Bruce Lefroy Centre, Murdoch Childrens Research Institute Accession: SCV001879319.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (Jun 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002064394.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: 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 … (more) 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. (less)
Pathogenic (Apr 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Sialic acid storage disease, severe infantile type Salla disease Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894394.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Jun 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020634.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Salla disease Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004201204.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jul 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198252.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Salla disease Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803591.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (3) PubMed: 10947946‚ 10581036‚ 21781115 Comment: 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 … (more) 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. (less)
Pathogenic (Sep 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Salla disease Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002027583.1 First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021
Pathogenic (Oct 04, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000490800.4 First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Salla disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000832695.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (9) PubMed: 28492532‚ 10581036‚ 10947946‚ 12794688‚ 12359136‚ 15510212‚ 15516337‚ 18695252‚ 21781115 Comment: 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 … (more) 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. (less)
Pathogenic (Feb 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001250035.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Jan 14, 2005)	no assertion criteria provided Method: literature only	SALLA DISEASE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026149.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 25, 2015	Publications: PubMed (6) PubMed: 10581036‚ 10947946‚ 12794687‚ 12794688‚ 15510212‚ 15516337 Comment on evidence: In 5 Finnish patients with classic Salla disease (SD; 604369), Verheijen et al. (1999) found an arg39-to-cys (R39C) missense mutation caused by a homozygous C-to-T … (more) In 5 Finnish patients with classic Salla disease (SD; 604369), Verheijen et al. (1999) found an arg39-to-cys (R39C) missense mutation caused by a homozygous C-to-T transition at nucleotide 115 of the SLC17A5 gene. Aula et al. (2000) found that the homozygous R39C mutation was associated with a milder phenotype (Salla disease). In monozygotic twin girls living in North America and apparently without Finnish ancestry, Martin et al. (2003) described Salla disease caused by the arg39-to-cys mutation. Their clinical histories were typical of the insidious onset and protracted course of Salla disease as described in Finnish patients with the R39C mutation. Their neonatal period was normal and hypotonia with mild delays and gross motor abilities became obvious only at the age of approximately 1 year. The hypotonia progressed to spasticity, as is often the case in Salla disease. Ocular nystagmus, often described as a common childhood feature of Salla disease, was absent in the twins. However, both girls demonstrated truncal ataxia, another prominent feature of Salla disease. Initial language delay and later language loss provided evidence of the progressive nature of the disorder. Neurologic progression often becomes evident as intelligence declines into adulthood to a point at which the IQ rarely exceeds 20. Although the facies of the twins appeared somewhat coarse, facial coarseness is not typically described in Salla disease until adulthood. Generalized skeletal abnormalities such as dysostosis multiplex, typical of many other lysosomal storage diseases including infantile free sialic acid storage disease, are not seen in Salla disease. Kleta et al. (2003) found the R39C mutation typical of Salla disease in compound heterozygous state with the 15-bp deletion (604322.0007) typical of ISSD, in a North American patient with 'intermediate severe' Salla disease. Functional expression studies showed that the R39C mutant protein retained some residual transport activity (Morin et al., 2004 and Wreden et al., 2005). (less)
Pathogenic (Jan 06, 2020)	no assertion criteria provided Method: curation	Salla disease Affected status: unknown Allele origin: germline	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142364.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020	Comment: 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 … (more) 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. (less)
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Salla disease Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001453518.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001742960.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001973812.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
not provided (-)	no classification provided Method: literature only	Sialic acid storage disease, severe infantile type Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000041226.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 20301643‚ 10947946 BookShelf: NBK1470 BookShelf: NBK1470
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Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Free Sialic Acid Storage Disorders.	Adam MP	-	2020	PMID: 20301643
Functional characterization of vesicular excitatory amino acid transport by human sialin.	Miyaji T	Journal of neurochemistry	2011	PMID: 21781115
Identification of a vesicular aspartate transporter.	Miyaji T	Proceedings of the National Academy of Sciences of the United States of America	2008	PMID: 18695252
Homozygosity for the p.K136E mutation in the SLC17A5 gene as cause of an Italian severe Salla disease.	Biancheri R	Neurogenetics	2005	PMID: 16170568
Varied mechanisms underlie the free sialic acid storage disorders.	Wreden CC	The Journal of biological chemistry	2005	PMID: 15516337
Functional characterization of wild-type and mutant human sialin.	Morin P	The EMBO journal	2004	PMID: 15510212
Biochemical and molecular analyses of infantile free sialic acid storage disease in North American children.	Kleta R	American journal of medical genetics. Part A	2003	PMID: 12794688
Sialic acid storage disease of the Salla phenotype in American monozygous twin female sibs.	Martin RA	American journal of medical genetics. Part A	2003	PMID: 12794687
Unraveling the molecular pathogenesis of free sialic acid storage disorders: altered targeting of mutant sialin.	Aula N	Molecular genetics and metabolism	2002	PMID: 12359136
Phenotypic spectrum of Salla disease, a free sialic acid storage disorder.	Varho TT	Pediatric neurology	2002	PMID: 11992753
The spectrum of SLC17A5-gene mutations resulting in free sialic acid-storage diseases indicates some genotype-phenotype correlation.	Aula N	American journal of human genetics	2000	PMID: 10947946
A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases.	Verheijen FW	Nature genetics	1999	PMID: 10581036
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SLC17A5	-	-	-	-
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Text-mined citations for rs80338794 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80338794 ...