rs772652517

Positions:

chr11-20636322-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F547L) has been classified 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:4

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 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-20636323-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1464961.Status of the report is criteria_provided_single_submitter, 1 stars.

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/exons	MANE
SLC6A5	NM_004211.5 linkuse as main transcript	c.1640T>C	p.Phe547Ser	missense_variant	11/16	ENST00000525748.6
SLC6A5	NM_001318369.2 linkuse as main transcript	c.938T>C	p.Phe313Ser	missense_variant	10/15
SLC6A5	XM_017018544.3 linkuse as main transcript	c.764T>C	p.Phe255Ser	missense_variant	7/12
SLC6A5	XR_007062528.1 linkuse as main transcript	n.1018T>C		non_coding_transcript_exon_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A5	ENST00000525748.6 linkuse as main transcript	c.1640T>C	p.Phe547Ser	missense_variant	11/16	1	NM_004211.5	P1	Q9Y345-1
SLC6A5	ENST00000298923.11 linkuse as main transcript	c.*937T>C		3_prime_UTR_variant, NMD_transcript_variant	10/15	1
SLC6A5	ENST00000528440.1 linkuse as main transcript	n.171T>C		non_coding_transcript_exon_variant	3/8	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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperekplexia 3

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	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; Invitae). ClinVar contains an entry for this variant (Variation ID: 540366). 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 SLC6A5 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	The SLC6A5 c.1640T>C; p.Phe547Ser variant has been found 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 also reported in ClinVar (Variation ID: 540366). 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). 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

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2022

Published functional studies demonstrate that p.(F547S) has a negative effect on protein function (Carta et al., 2012); 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: 34266921, 24030948, 22700964, 29859229) -

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

MutationTaster

Benign

1.0

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