NM_004211.5(SLC6A5):c.1472A>G (p.Tyr491Cys) AND Hyperekplexia 3

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 8, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000006119.8

Allele description [Variation Report for NM_004211.5(SLC6A5):c.1472A>G (p.Tyr491Cys)]

NM_004211.5(SLC6A5):c.1472A>G (p.Tyr491Cys)

Gene:

SLC6A5:solute carrier family 6 member 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.1

Genomic location:

Preferred name:

NM_004211.5(SLC6A5):c.1472A>G (p.Tyr491Cys)

HGVS:

NC_000011.10:g.20628056A>G
NG_013086.2:g.33657A>G
NM_001318369.2:c.770A>G
NM_004211.5:c.1472A>GMANE SELECT
NP_001305298.1:p.Tyr257Cys
NP_004202.4:p.Tyr491Cys
NC_000011.9:g.20649602A>G
NM_004211.3:c.1472A>G
Q9Y345:p.Tyr491Cys

Nucleotide change:

A1472G

Protein change:

Y257C; TYR491CYS

Links:

UniProtKB: Q9Y345#VAR_044172; OMIM: 604159.0003; dbSNP: rs121908494

NCBI 1000 Genomes Browser:

rs121908494

Molecular consequence:

NM_001318369.2:c.770A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004211.5:c.1472A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hyperekplexia 3 (HKPX3)
Synonyms:: HYPEREKPLEXIA 3, AUTOSOMAL RECESSIVE; HYPEREKPLEXIA 3, AUTOSOMAL DOMINANT
Identifiers:: MONDO: MONDO:0013827; MedGen: C3553288; Orphanet: 3197; OMIM: 614618

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000026301	OMIM	no assertion criteria provided	Pathogenic (Jul 1, 2006)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000054571	GeneReviews	no assertion criteria provided	pathologic (Oct 4, 2012)	not provided	curation
SCV003515886	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 8, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16751771, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000026301

OMIM

no assertion criteria provided

Pathogenic
(Jul 1, 2006)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000054571

GeneReviews

no assertion criteria provided

pathologic
(Oct 4, 2012)

not provided

curation

SCV003515886

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 8, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease.

Rees MI, Harvey K, Pearce BR, Chung SK, Duguid IC, Thomas P, Beatty S, Graham GE, Armstrong L, Shiang R, Abbott KJ, Zuberi SM, Stephenson JB, Owen MJ, Tijssen MA, van den Maagdenberg AM, Smart TG, Supplisson S, Harvey RJ.

Nat Genet. 2006 Jul;38(7):801-6. Epub 2006 Jun 4.

PubMed [citation]

PMID:: 16751771
PMCID:: PMC3204411

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From OMIM, SCV000026301.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a patient with hyperekplexia-3 (HKPX3; 614618) from the United States, Rees et al. (2006) found compound heterozygosity for a missense and a nonsense mutation in the SLC6A5 gene: a 1472A-G transition in exon 9 resulting in a tyr491-to-cys substitution (Y491C), and a 1888C-T transition in exon 13 resulting in a gln630-to-stop substitution (Q630X; 604159.0004). The parents were unaffected but declined participation in molecular studies.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000054571.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

Converted during submission to Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not provided	not provided	not provided	not provided	Assert pathogenicity		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003515886.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 491 of the SLC6A5 protein (p.Tyr491Cys). This variant is present in population databases (rs121908494, gnomAD 0.003%). This missense change has been observed in individual(s) with hyperekplexia (PMID: 16751771). ClinVar contains an entry for this variant (Variation ID: 5763). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SLC6A5 function (PMID: 16751771). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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