rs761533681

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM5PP3PP5_Very_Strong

The NM_003038.5(SLC1A4):c.1369C>T(p.Arg457Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,611,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R457Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

SLC1A4
NM_003038.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 5.95

Publications

11 publications found

Variant links:

Genes affected

SLC1A4 (HGNC:10942): (solute carrier family 1 member 4) The protein encoded by this gene is a sodium-dependent neutral amino acid transporter for alanine, serine, cysteine, and threonine. Defects in this gene have been associated with developmental delay, microcephaly, and intellectual disability. [provided by RefSeq, Jan 2017]

SLC1A4 links:

LINC02245 (HGNC:53134): (long intergenic non-protein coding RNA 2245)

LINC02245 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-65020917-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1685441.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.801

PP5

Variant 2-65020916-C-T is Pathogenic according to our data. Variant chr2-65020916-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 372158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC1A4	NM_003038.5 link	c.1369C>T	p.Arg457Trp	missense_variant	Exon 8 of 8	ENST00000234256.4	NP_003029.2
SLC1A4	NM_001348406.2 link	c.709C>T	p.Arg237Trp	missense_variant	Exon 8 of 8		NP_001335335.1
SLC1A4	NM_001348407.2 link	c.709C>T	p.Arg237Trp	missense_variant	Exon 8 of 8		NP_001335336.1
SLC1A4	NM_001193493.2 link	c.475C>T	p.Arg159Trp	missense_variant	Exon 7 of 7		NP_001180422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC1A4	ENST00000234256.4 link	c.1369C>T	p.Arg457Trp	missense_variant	Exon 8 of 8	1	NM_003038.5	ENSP00000234256.3		P43007-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD2 exomes

AF:

0.000123

AC:

AN:

251166

AF XY:

0.0000810

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1459754

Hom.:

Cov.:

AF XY:

0.0000262

AC XY:

AN XY:

726322

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33446

American (AMR)

AF:

0.000693

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1110066

Other (OTH)

AF:

0.0000166

AC:

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41418

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000533

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome

Pathogenic:6

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

This variant was identified in an individual with developmental delay, microcephaly, corpus callosum agenesis, hypomyelination. -

Apr 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 03, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SLC1A4 c.1369C>T (p.Arg457Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251166 control chromosomes (gnomAD). c.1369C>T has been reported in the literature in the homozygous state in two unrelated individuals affected with Spastic Tetraplegia-Thin Corpus Callosum-Progressive Postnatal Microcephaly Syndrome (Damseh_2015, Eldomery_2017). These data indicate that the variant is likely to be associated with disease. A functional study found that although the variant protein is expressed at a similar level as the WT protein at the plasma membrane, it has no detectable transport activity (Damseh_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26041762, 28327206). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=4)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 15, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 16, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 30, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372158 /PMID: 26041762). A different missense change at the same codon (p.Arg457Gln) has been reported to be associated with SLC1A4 related disorder (ClinVar ID: VCV001685441). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:3

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC1A4: PM2, PM3, PP3, PS4:Supporting -

Sep 10, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate p.R457W impairs transporter activity (PMID: 26041762); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31763347, 26041762, Stehantsev2021[article], 33310157, 34174466, 37194416, 28327206, 2837306) -

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 457 of the SLC1A4 protein (p.Arg457Trp). This variant is present in population databases (rs761533681, gnomAD 0.05%). This missense change has been observed in individuals with cerebral palsy and/or spastic tetraplegia, thin corpus callosum, and progressive microcephaly (PMID: 2837306, 26041762, 33528536; internal data). ClinVar contains an entry for this variant (Variation ID: 372158). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SLC1A4 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC1A4 function (PMID: 26041762). This variant disrupts the p.Arg457 amino acid residue in SLC1A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC1A4-related conditions (PMID: 26041762, 34174466), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Inborn genetic diseases

Pathogenic:1

May 04, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

.;D

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Pathogenic

4.4

.;H

PhyloP100

5.9

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.4

D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

.;D

Vest4

0.95

MutPred

0.69

.;Gain of sheet (P = 0.0085);

MVP

0.90

MPC

1.1

ClinPred

0.99

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.98

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over