rs548065551

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_177550.5(SLC13A5):c.1280C>T(p.Ser427Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000873 in 1,602,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 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. S427S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

SLC13A5
NM_177550.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.51

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 links:

(HGNC:):

links:

C17orf100 (HGNC:34494): (chromosome 17 open reading frame 100)

C17orf100 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

PP5

Variant 17-6690936-G-A is Pathogenic according to our data. Variant chr17-6690936-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-6690936-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC13A5	NM_177550.5 linkuse as main transcript	c.1280C>T	p.Ser427Leu	missense_variant	10/12	ENST00000433363.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC13A5	ENST00000433363.7 linkuse as main transcript	c.1280C>T	p.Ser427Leu	missense_variant	10/12	1	NM_177550.5	P1	Q86YT5-1
	ENST00000634558.1 linkuse as main transcript	n.662+909G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000411

AC:

AN:

243460

Hom.:

AF XY:

0.00

AC XY:

AN XY:

131128

show subpopulations

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:

0.00

Gnomad NFE exome

AF:

0.00000909

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000896

AC:

AN:

1450788

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720146

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000118

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000327

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 25

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2015	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 02, 2021	The p.Ser427Leu variant in SLC13A5 has been reported in 9 individuals with developmental and epileptic encephalopathy (PMID: 27913086, 26384929, 33063863, 27652284), segregated with disease in 3 affected relatives from 3 families (PMID: 27913086, 26384929), and has been identified in in 0.0009% (1/110,052) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs548065551). 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. This variant has also been reported in ClinVar (Variation ID#: 218170) and has been interpreted as pathogenic by OMIM and Invitae. Of the 9 affected individuals, 2 were homozygotes, 2 were compound heterozygotes that carried a reported pathogenic or likely pathogenic variant in trans, which increases the likelihood that the p.Ser427Leu variant is pathogenic (VariationID: 140753, 140752; PMID: 27913086, 27652284, 33063863). In vitro functional studies provide some evidence that the p.Ser427Leu variant may slightly impact protein function (PMID: 26384929). 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. 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: PM2_supporting, PM3, PP1_strong, PS3_supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 04, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC13A5 function (PMID: 26384929). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 427 of the SLC13A5 protein (p.Ser427Leu). This variant is present in population databases (rs548065551, gnomAD no frequency). This missense change has been observed in individuals with clinical features of epileptic encephalopathy (PMID: 26384929, 27913086). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218170). 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. -

SLC13A5-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2024

The SLC13A5 c.1280C>T variant is predicted to result in the amino acid substitution p.Ser427Leu. This variant was reported in the homozygous or compound heterozygous state in several families with epileptic encephalopathy or neonatal seizures (Weeke et al. 2017. PubMed ID: 27913086; Hardies et al. 2015. PubMed ID: 26384929). Functional studies showed that p.Ser427Leu substitution leads to a loss of citrate uptake due to a loss-of-function mechanism. Taken together, we classify this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.37

T;.;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Benign

-0.88

MutationAssessor

Pathogenic

4.4

H;.;.;H

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-5.6

D;.;D;.

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.98

MVP

0.59

MPC

0.90

ClinPred

1.0

GERP RS

5.1

Varity_R

0.93

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over