rs772652517

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_004211.5(SLC6A5):c.1640T>C(p.Phe547Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000546 in 1,612,442 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

SLC6A5
NM_004211.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.02

Variant links:

Genes affected

SLC6A5 (HGNC:11051): (solute carrier family 6 member 5) This gene encodes a sodium- and chloride-dependent glycine neurotransmitter transporter. This integral membrane glycoprotein is responsible for the clearance of extracellular glycine during glycine-mediated neurotransmission. This protein is found in glycinergic axons and maintains a high presynaptic pool of neurotransmitter at glycinergic synapses. Mutations in this gene cause hyperekplexia; a heterogenous neurological disorder characterized by exaggerated startle responses and neonatal apnea. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

SLC6A5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 11-20636322-T-C is Pathogenic according to our data. Variant chr11-20636322-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 540366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A5	NM_004211.5 link	c.1640T>C	p.Phe547Ser	missense_variant	Exon 11 of 16	ENST00000525748.6	NP_004202.4	Q9Y345-1Q4VAM4Q4VAM6
SLC6A5	NM_001318369.2 link	c.938T>C	p.Phe313Ser	missense_variant	Exon 10 of 15		NP_001305298.1	Q9Y345-2Q4VAM4
SLC6A5	XM_017018544.3 link	c.764T>C	p.Phe255Ser	missense_variant	Exon 7 of 12		XP_016874033.1
SLC6A5	XR_007062528.1 link	n.1018T>C		non_coding_transcript_exon_variant	Exon 8 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC6A5	ENST00000525748.6 link	c.1640T>C	p.Phe547Ser	missense_variant	Exon 11 of 16	1	NM_004211.5	ENSP00000434364.2	Q9Y345-1
SLC6A5	ENST00000298923.11 link	n.*937T>C		non_coding_transcript_exon_variant	Exon 10 of 15	1		ENSP00000298923.7	J3KNC4
SLC6A5	ENST00000298923.11 link	n.*937T>C		3_prime_UTR_variant	Exon 10 of 15	1		ENSP00000298923.7	J3KNC4
SLC6A5	ENST00000528440.1 link	n.171T>C		non_coding_transcript_exon_variant	Exon 3 of 8	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

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:

0.0000199

AC:

AN:

251352

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000596

AC:

AN:

1460250

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

726614

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000693

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

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:

0.0000658

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperekplexia 3

Pathogenic:3

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 547 of the SLC6A5 protein (p.Phe547Ser). This variant is present in population databases (rs772652517, gnomAD 0.007%). This missense change has been observed in individuals with hyperekplexia (PMID: 22700964; internal data). ClinVar contains an entry for this variant (Variation ID: 540366). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC6A5 protein function. For these reasons, this variant has been classified as Pathogenic. -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC6A5 c.1640T>C; p.Phe547Ser variant (rs772652517, ClinVar Variation ID: 540366) has been reported in the literature in multiple complex heterozygous individuals with hyperekplexia and function analysis found this variant is deficient in glycine uptake (Carta 2012, Neupert 2021). This variant is only observed on five alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.965). This variant is also reported in ClinVar (Variation ID: 540366). Based on available information, this variant is considered to be likely pathogenic. References: Carta E et al. Mutations in the GlyT2 gene (SLC6A5) are a second major cause of startle disease. J Biol Chem. 2012 Aug 17;287(34):28975-85. PMID: 22700964. Neupert DG et al. Teaching Video NeuroImage: Hereditary Hyperekplexia Mimicking Tonic Seizures in an Infant. Neurology. 2021 Nov 30;97(22):e2248-e2249. PMID: 34266921. -

not provided

Pathogenic:1

Nov 07, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that p.(F547S) has a negative effect on protein function (PMID: 22700964); 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: 24030948, 29859229, 34266921, 22700964) -

SLC6A5-related disorder

Pathogenic:1

Sep 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SLC6A5 c.1640T>C variant is predicted to result in the amino acid substitution p.Phe547Ser. This variant has been reported in the compound heterozygous state in multiple individuals with hyperekplexia (Carta et al. 2012. PubMed ID: 22700964; Thomas et al. 2013. PubMed ID: 24030948; Neupert et al. 2021. PubMed ID: 34266921). This variant has been reported to segregate with hyperekplexia in two different consanguineous families (Internal Data, PreventionGenetics). In vitro functional studies indicate that this variant impacts protein function (Carta et al. 2012. PubMed ID: 22700964) and in silico analyses suggest this variant changes the position of key residues and the binding site resulting in a more severe phenotype (Thomas et al. 2013. PubMed ID: 24030948; Lopez-Corcuera et al. 2019. PubMed ID: 29859229). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.2

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-8.0

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.99

MVP

0.98

MPC

1.0

ClinPred

1.0

GERP RS

5.3

Varity_R

0.95

gMVP

0.98

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

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