Likely inborn error of metabolism

Gene: SLC6A5

Green List (high evidence)

Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic variants with hyperekplexia 3. This gene encodes a metabolite transporter and is rated definitive by General Inborn Errors of Metabolism GCEP for biallelic variants. This gene should therefore be promoted to green rating on R98 in the next GMS update.

Created: 23 Apr 2026, 12:40 p.m. | Last Modified: 23 Apr 2026, 12:40 p.m.

Panel Version: 8.113

PMID:16751771 (2006) reported seven patients from six unrelated families presenting with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnoea episodes. Of these, six patients from five families were identified with homozygous or compound heterozygous variants in SLC6A5 gene. The seventh patient was identified with a heterozygous variant in the same gene. There is also functional evidence available for the variants, showing that they result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites.
The SLC6A5 gene encodes the Sodium- and chloride-dependent glycine transporter 2 (GlyT2), a membrane protein responsible for re-uptake of glycine in the spinal cord and brainstem.

PMID:22753417 (2012) reported the identification of a new dominant SLC6A5 variant (p.Tyr705Cys) via single gene sequencing in eight individuals from three families in two cohorts of hyperekplexia patients. As well as classical hyperekplexia symptoms, certain individuals exhibited abnormal respiration, facial dysmorphism, delayed motor development, or intellectual disability. This may be due to a complex phenotype caused by the variant or to the presence of additional unknown variants. There is also functional evidence available for this variant.

Both monoallelic and biallelic variants are associated with hyperekplexia 3 (MIM #614618) in OMIM (last accessed 23 April 2026). In addition, biallelic variants are associated with hyperekplexia 3 (MONDO:0013827) with 'Definitive' rating by General Inborn Errors of Metabolism GCEP in ClinGen.
Sources: Literature

Created: 23 Apr 2026, 12:28 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Hyperekplexia 3, OMIM:614618; hyperekplexia 3, MONDO:0013827

Publications

• 16751771
• 22753417