rs80338794

Positions:

• chr6-73644583-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 15P and 1B. PM1 PM2 PM5 PP3 PP5_Very_Strong BP4

The NM_012434.5(SLC17A5):​c.115C>T​(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R39H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (1 hom.)
• Consequence: SLC17A5 NM_012434.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 9.27

Genes affected

SLC17A5 (HGNC:10933): (solute carrier family 17 member 5) This gene encodes a membrane transporter that exports free sialic acids that have been cleaved off of cell surface lipids and proteins from lysosomes. Mutations in this gene cause sialic acid storage diseases, including infantile sialic acid storage disorder and and Salla disease, an adult form. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 40) in uniprot entity S17A5_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_012434.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-73644582-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 6-73644583-G-A is Pathogenic according to our data. Variant chr6-73644583-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-73644583-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.085522145). . Strength limited to SUPPORTING due to the PP5.

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: 69 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000827 AC: 208 AN: 251452 Hom.: 0 AF XY: 0.000809 AC XY: 110 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00614

Gnomad NFE exome AF: 0.000659

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000355 AC: 519 AN: 1461738 Hom.: 1 Cov.: 31 AF XY: 0.000347 AC XY: 252 AN XY: 727172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00459

Gnomad4 NFE exome AF: 0.000227

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.000658 AC XY: 49 AN XY: 74454

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000307 Hom.: 0

Bravo AF: 0.000181

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000782 AC: 95

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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 Tübingen	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:2 Other: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MVP		0.82
MPC		0.86
ClinPred		0.75	D
GERP RS		5.6
Varity_R		0.94
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338794; hg19: chr6-74354306; COSMIC: COSV105251670; COSMIC: COSV105251670;