rs886037943

Positions:

• chr11-35315079-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_004171.4(SLC1A2):​c.254T>C​(p.Leu85Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SLC1A2 NM_004171.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.28

Genes affected

SLC1A2 (HGNC:10940): (solute carrier family 1 member 2) This gene encodes a member of a family of solute transporter proteins. The membrane-bound protein is the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. Improper regulation of this gene is thought to be associated with several neurological disorders. Alternatively spliced transcript variants of this gene have been identified. [provided by RefSeq, Jun 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 11-35315079-A-G is Pathogenic according to our data. Variant chr11-35315079-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 254266.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr11-35315079-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC1A2	NM_004171.4	c.254T>C	p.Leu85Pro	missense_variant	3/11	ENST00000278379.9	NP_004162.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC1A2	ENST00000278379.9	c.254T>C	p.Leu85Pro	missense_variant	3/11	1	NM_004171.4	ENSP00000278379	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 85 of the SLC1A2 protein (p.Leu85Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with epileptic encephalopathy (PMID: 27476654, 30937933). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 254266). 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 SLC1A2 protein function. Experimental studies have shown that this missense change affects SLC1A2 function (PMID: 30937933, 34961934). For these reasons, this variant has been classified as Pathogenic. -

Developmental and epileptic encephalopathy, 41 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 12, 2013

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The c.254T>C (p.L85P) alteration is located in exon 3 (coding exon 3) of the SLC1A2 gene. This alteration results from a T to C substitution at nucleotide position 254, causing the leucine (L) at amino acid position 85 to be replaced by a proline (P). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in one individual with features consistent with SLC1A2-related developmental and epileptic encephalopathy (Myers, 2016). This amino acid position is highly conserved in available vertebrate species. Functional studies show that the p.L85P alteration decreases transport activity (Stergachis, 2019; Qu, 2022; Kovermann, 2022). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D;D;.;D;.;.;.;.;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.6	H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;H;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.3	D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0010	D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.99
MutPred		0.85		Loss of stability (P = 0.0275);Loss of stability (P = 0.0275);.;.;Loss of stability (P = 0.0275);.;.;.;.;.;.;.;.;.;.;Loss of stability (P = 0.0275);Loss of stability (P = 0.0275);.;Loss of stability (P = 0.0275);.;.;.;.;Loss of stability (P = 0.0275);Loss of stability (P = 0.0275);Loss of stability (P = 0.0275);Loss of stability (P = 0.0275);
MVP		0.90
MPC		1.9
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.99

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: rs886037943; hg19: chr11-35336626;