NM_177550.5(SLC13A5):c.425C>T (p.Thr142Met) AND Developmental and epileptic encephalopathy, 25

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jan 25, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000202397.25

Allele description [Variation Report for NM_177550.5(SLC13A5):c.425C>T (p.Thr142Met)]

NM_177550.5(SLC13A5):c.425C>T (p.Thr142Met)

Gene:

SLC13A5:solute carrier family 13 member 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_177550.5(SLC13A5):c.425C>T (p.Thr142Met)

Other names:

NM_177550.4(SLC13A5):c.425C>T; p.Thr142Met

HGVS:

NC_000017.11:g.6704000G>A
NG_034220.1:g.14422C>T
NM_001143838.3:c.425C>T
NM_001284509.2:c.374C>T
NM_001284510.2:c.296C>T
NM_177550.5:c.425C>TMANE SELECT
NP_001137310.1:p.Thr142Met
NP_001271438.1:p.Thr125Met
NP_001271439.1:p.Thr99Met
NP_808218.1:p.Thr142Met
NP_808218.1:p.Thr142Met
LRG_1020t1:c.425C>T
LRG_1020:g.14422C>T
LRG_1020p1:p.Thr142Met
NC_000017.10:g.6607319G>A
NM_177550.4:c.425C>T

Protein change:

T125M; THR142MET

Links:

OMIM: 608305.0007; dbSNP: rs761917087

NCBI 1000 Genomes Browser:

rs761917087

Molecular consequence:

NM_001143838.3:c.425C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001284509.2:c.374C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001284510.2:c.296C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_177550.5:c.425C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Developmental and epileptic encephalopathy, 25 (DEE25)
Synonyms:: Epileptic encephalopathy, early infantile, 25; Developmental and epileptic encephalopathy 25, with amelogenesis imperfecta; Epileptic encephalopathy, early infantile, 25, with amelogenesis imperfecta
Identifiers:: MONDO: MONDO:0014392; MedGen: C4014621; Orphanet: 442835; OMIM: 615905

Recent activity

Clear Turn Off Turn On

Homo sapiens hypothetical protein FLJ20128 (FLJ20128), mRNA
Homo sapiens hypothetical protein FLJ20128 (FLJ20128), mRNA
gi|8923130|ref|NM_017679.1|

Nucleotide

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000257430	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2015)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000826730	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27600704, 26384929, 28492532
SCV001430127	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Jun 11, 2019)	germline	clinical testing	Citation Link,
SCV001999889	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 2, 2021)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV002055652	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

SLC13A5 is the second gene associated with Kohlschütter-Tönz syndrome.

Schossig A, Bloch-Zupan A, Lussi A, Wolf NI, Raskin S, Cohen M, Giuliano F, Jurgens J, Krabichler B, Koolen DA, de Macena Sobreira NL, Maurer E, Muller-Bolla M, Penzien J, Zschocke J, Kapferer-Seebacher I.

J Med Genet. 2017 Jan;54(1):54-62. doi: 10.1136/jmedgenet-2016-103988. Epub 2016 Sep 6.

PubMed [citation]

PMID:: 27600704

Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia.

Hardies K, de Kovel CG, Weckhuysen S, Asselbergh B, Geuens T, Deconinck T, Azmi A, May P, Brilstra E, Becker F, Barisic N, Craiu D, Braun KP, Lal D, Thiele H, Schubert J, Weber Y, van 't Slot R, Nürnberg P, Balling R, Timmerman V, Lerche H, et al.

Brain. 2015 Nov;138(Pt 11):3238-50. doi: 10.1093/brain/awv263. Epub 2015 Sep 17.

PubMed [citation]

PMID:: 26384929

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000257430.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

For discussion of the c.425C-T transition (c.425C-T, NM_177550.4), resulting in a thr142-to-met (T142M) substitution, in the SLC13A5 gene that was found in compound heterozygous state in 3 sibs with developmental and epileptic encephalopathy-25 with amelogenesis imperfecta (DEE25; 615905) by Hardies et al. (2015), see 608305.0001.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000826730.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 142 of the SLC13A5 protein (p.Thr142Met). This variant is present in population databases (rs761917087, gnomAD 0.003%). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy and amelogenesis imperfecta and SLC13A5-related conditions (PMID: 26384929, 27600704; Invitae). 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. ClinVar contains an entry for this variant (Variation ID: 218173). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC13A5 protein function. Experimental studies have shown that this missense change affects SLC13A5 function (PMID: 26384929). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV001430127.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	blood	not provided		1	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001999889.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

The p.Thr142Met variant in SLC13A5 has been reported in 9 individuals across 5 families (PMID: 26384929, 32551328, 33063863, 29138412), and has been identified in in 0.003% (1/30574) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs761917087). 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 5 families, one had 3 compound heterozygous relatives that carried reported pathogenic variants in trans, two had 2 homozygous relatives, and two had 2 compound heterozygotes that carried a variant of uncertain significance in trans, which increases the likelihood that the p.Thr227Met variant is pathogenic (PMID: 26384929, 32551328, 33063863, 29138412). This variant has also been reported in ClinVar (Variation ID#: 218173) and has been interpreted as likely pathogenic by Invitae and pathogenic by OMIM and Institute of Human Genetics (Klinikum rechts der Isar). In vitro functional studies provide some evidence that the p.Thr142Met variant may slightly impact protein function (PMID: 26384929, 33040525). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Thr142Met 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: 33040525). 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, 25. ACMG/AMP Criteria applied: PM2_supporting, PM3, PP1_strong, PS3_supporting, PM1_supporting (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002055652.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

ClinVar

Relating variation to medicine