rs587777577

Positions:

• chr17-6703006-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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. 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. 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a strand (size 4) in uniprot entity S13A5_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_177550.5
• PM2: Very rare variant in population databases, with high coverage
• 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 ClinVar as [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 Lovd as [Pathogenic]. Variant chr17-6703006-G-A is described in Lovd as [Likely_pathogenic]. Variant chr17-6703006-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC13A5	NM_177550.5	c.680C>T	p.Thr227Met	missense_variant	5/12	ENST00000433363.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC13A5	ENST00000433363.7	c.680C>T	p.Thr227Met	missense_variant	5/12	1	NM_177550.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152262 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251128 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135748

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461836 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74388

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: 0.0000941

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 25 Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	-	- -
Pathogenic, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	This variant was identified as compound heterozygous in an individual with epileptic encephalopathy. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 29, 2023	ClinVar contains an entry for this variant (Variation ID: 140753). 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). This variant is present in population databases (rs587777577, gnomAD 0.004%). 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. 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. Experimental studies have shown that this missense change affects SLC13A5 function (PMID: 26384929, 27261973). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 02, 2021	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Undetermined early-onset epileptic encephalopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 23, 2018

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	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	4.5	H;.;.;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
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	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs587777577; hg19: chr17-6606325; COSMIC: COSV53424374; COSMIC: COSV53424374;