NM_177550.5(SLC13A5):c.680C>T (p.Thr227Met) AND Undetermined early-onset epileptic encephalopathy

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 23, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000826127.4

Allele description [Variation Report for NM_177550.5(SLC13A5):c.680C>T (p.Thr227Met)]

NM_177550.5(SLC13A5):c.680C>T (p.Thr227Met)

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.680C>T (p.Thr227Met)

Other names:

NM_177550.4(SLC13A5):c.680C>T

HGVS:

NC_000017.11:g.6703006G>A
NG_034220.1:g.15416C>T
NM_001143838.3:c.680C>T
NM_001284509.2:c.629C>T
NM_001284510.2:c.551C>T
NM_177550.5:c.680C>TMANE SELECT
NP_001137310.1:p.Thr227Met
NP_001271438.1:p.Thr210Met
NP_001271439.1:p.Thr184Met
NP_808218.1:p.Thr227Met
NP_808218.1:p.Thr227Met
LRG_1020t1:c.680C>T
LRG_1020:g.15416C>T
LRG_1020p1:p.Thr227Met
NC_000017.10:g.6606325G>A
NM_001143838.1:c.680C>T
NM_177550.3:c.680C>T
NM_177550.4:c.680C>T
p.Thr227Met

Protein change:

T184M; THR227MET

Links:

OMIM: 608305.0002; dbSNP: rs587777577

NCBI 1000 Genomes Browser:

rs587777577

Molecular consequence:

NM_001143838.3:c.680C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001284509.2:c.629C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001284510.2:c.551C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_177550.5:c.680C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Undetermined early-onset epileptic encephalopathy
Identifiers:: MONDO: MONDO:0018614; MedGen: C5680057

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000967638	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Mar 23, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24995870, 27261973, 26384929, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000967638

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Mar 23, 2018)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in SLC13A5 cause autosomal-recessive epileptic encephalopathy with seizure onset in the first days of life.

Thevenon J, Milh M, Feillet F, St-Onge J, Duffourd Y, Jugé C, Roubertie A, Héron D, Mignot C, Raffo E, Isidor B, Wahlen S, Sanlaville D, Villeneuve N, Darmency-Stamboul V, Toutain A, Lefebvre M, Chouchane M, Huet F, Lafon A, de Saint Martin A, Lesca G, et al.

Am J Hum Genet. 2014 Jul 3;95(1):113-20. doi: 10.1016/j.ajhg.2014.06.006.

PubMed [citation]

PMID:: 24995870
PMCID:: PMC4085634

Mutations in the Na(+)/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay.

Klotz J, Porter BE, Colas C, Schlessinger A, Pajor AM.

Mol Med. 2016 May 26;22. doi: 10.2119/molmed.2016.00077.

PubMed [citation]

PMID:: 27261973
PMCID:: PMC5023510

See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967638.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

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

#	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		1	not provided	1	not provided

Last Updated: Oct 8, 2024

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