rs886039765

Positions:

• chr2-107992121-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_021815.5(SLC5A7):​c.194G>A​(p.Gly65Glu) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC5A7 NM_021815.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.60

Genes affected

SLC5A7 (HGNC:14025): (solute carrier family 5 member 7) This gene encodes a sodium ion- and chloride ion-dependent high-affinity transporter that mediates choline uptake for acetylcholine synthesis in cholinergic neurons. The protein transports choline from the extracellular space into presynaptic terminals for synthesis into acetylcholine. Increased choline uptake results from increased density of this protein in synaptosomal plasma membranes in response to depolarization of cholinergic terminals. Dysfunction of cholinergic signaling has been implicated in various disorders including depression, attention-deficit disorder, and schizophrenia. An allelic variant of this gene is associated with autosomal dominant distal hereditary motor neuronopathy type VIIA. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC5A7	NM_021815.5	c.194G>A	p.Gly65Glu	missense_variant	3/9	ENST00000264047.3	NP_068587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC5A7	ENST00000264047.3	c.194G>A	p.Gly65Glu	missense_variant	3/9	1	NM_021815.5	ENSP00000264047.2
SLC5A7	ENST00000409059.5	c.194G>A	p.Gly65Glu	missense_variant	3/9	1		ENSP00000387346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 20 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 07, 2016

- -

Neuronopathy, distal hereditary motor, type 7A;C4310694:Congenital myasthenic syndrome 20 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 21, 2018

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change alters the sodium-dependent high-affinity choline transporter 1 activity (PMID: 27569547). This variant has been observed in an individual affected with autosomal recessive congenital myasthenic syndrome (PMID: 27569547). ClinVar contains an entry for this variant (Variation ID: 265761). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 65 of the SLC5A7 protein (p.Gly65Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.2	M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.7	D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.89		Loss of catalytic residue at G66 (P = 0.1399);Loss of catalytic residue at G66 (P = 0.1399);
MVP		0.96
MPC		2.2
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.99
gMVP		1.0

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: rs886039765; hg19: chr2-108608577; COSMIC: COSV105069071;