chr17-6703006-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_177550.5(SLC13A5):c.680C>T(p.Thr227Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T227T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SLC13A5
NM_177550.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 10.0

Publications

16 publications found

Variant links:

Genes affected

SLC13A5 (HGNC:23089): (solute carrier family 13 member 5) This gene encodes a protein belonging to the solute carrier family 13 group of proteins. This family member is a sodium-dependent citrate cotransporter that may regulate metabolic processes. Mutations in this gene cause early infantile epileptic encephalopathy 25. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2014]

SLC13A5 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 25
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
amelocerebrohypohidrotic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
pyridoxine-dependent epilepsy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC13A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 17-6703006-G-A is Pathogenic according to our data. Variant chr17-6703006-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 140753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6703006-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 140753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6703006-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 140753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6703006-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 140753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6703006-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 140753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6703006-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 140753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6703006-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 140753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6703006-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 140753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6703006-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 140753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6703006-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 140753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6703006-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 140753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6703006-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 140753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC13A5	NM_177550.5 link	c.680C>T	p.Thr227Met	missense_variant	Exon 5 of 12	ENST00000433363.7	NP_808218.1	Q86YT5-1Q68D44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC13A5	ENST00000433363.7 link	c.680C>T	p.Thr227Met	missense_variant	Exon 5 of 12	1	NM_177550.5	ENSP00000406220.2		Q86YT5-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251128

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41478

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 25

Pathogenic:8

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

This variant was identified as compound heterozygous in an individual with epileptic encephalopathy. -

Oct 05, 2019

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 02, 2021

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Thr227Met variant in SLC13A5 has been reported in at least 10 individuals with developmental and epileptic encephalopathy (PMID: 24995870, 26384929, 27261973, 27600704, 28673551, 27913086, 31231135, 32551328, 33063863), and has been identified in 0.004% (1/24960) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs140115503). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the 10 affected individuals, 3 of those were homozygotes and 5 were compound heterozygotes that carried reported pathogenic/likely pathogenic variants in trans or with unknown phase, which increases the likelihood that the p.Thr227Met variant is pathogenic (Variation ID#: 140752, 280534; PMID: 24995870, 27261973, 27600704, 28673551, 31231135). This variant has also been reported in ClinVar (Variation ID#: 140753) and has been interpreted as VUS by Invitae, likely pathogenic by Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine), and pathogenic by OMIM, Lupski Lab (Baylor-Hopkins CMG, Baylor College of Medicine), and Equipe Genetique des Anomalies du Developpement (Université de Bourgogne). In vitro functional studies provide some evidence that the p.Thr227Met variant may slightly impact protein function (PMID: 33040525, 26384929, 27261973). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Thr227Met variant is located in a region of SLC13A5 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 26384929, 27261973). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive developmental and epileptic encephalopathy. ACMG/AMP Criteria applied: PM3_strong, PM2_supporting, PP3, PS3_supporting, PM1_supporting (Richards 2015). -

Jul 15, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 04, 2025

Institute of Immunology and Genetics Kaiserslautern

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG Criteria: PS3, PM2, PM3, PP3, PP5; Variant was found in homozygous state. -

Aug 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC13A5 function (PMID: 26384929, 27261973). 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 SLC13A5 protein function. ClinVar contains an entry for this variant (Variation ID: 140753). This missense change has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 24995870, 26384929, 27261973, 27600704, 27913086, 28673551, 30525188, 32551328, 33063863). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs587777577, gnomAD 0.004%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 227 of the SLC13A5 protein (p.Thr227Met). -

Nov 01, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 21, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27600704, 31231135, 32551328, 26384929, 27261973, 30054523, 33063863, 30525188, 28673551, 24995870, 27913086) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Undetermined early-onset epileptic encephalopathy

Pathogenic:1

Mar 23, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Thr227Met variant in SLC13A5 has been reported in 4 individuals with epile ptic encephalopathy and segregated with the disease in 1 affected family member; 3 of these individuals were compound heterozygous for the variant and one of th em homozygous (Hardies 2015, Klotz 2016, Thevenon 2014). This variant has also b een reported in ClinVar (Variation ID# 140753). This variant has been identified in 0.002% (3/126,362) of European chromosomes by the Genome Aggregation Databas e (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587777577). Although this v ariant has been seen in the general population, its frequency is low enough to b e consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that the p.Thr227Met variant may impact the pr otein, though this information is not predictive enough to determine pathogenici ty. In vitro functional studies provide some evidence that the p.Thr227Met varia nt may impact protein function (Hardies 2015, Klotz 2016). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, t he p.Thr227Met variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3 _Strong, PS3_Supporting, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

T;.;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Benign

-0.85

MutationAssessor

Pathogenic

4.5

H;.;.;H

PhyloP100

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.0

D;.;D;.

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.97

MVP

0.70

MPC

0.98

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.94

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over