SLC6A5

Inheritance Pattern: AD

Disease ID:MONDO:0013827

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0013827

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0021022

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013827

Submitter: ClinGen

The gene SLC6A5 was first implicated in autosomal recessive hyperekplexia 3 in 2006 (Rees et al., PMID: 16751771). SLC6A5 encodes the glycine transporter GlyT2, which is predominantly expressed in presynaptic axons within the brainstem, spinal cord, and, to a lesser extent, the cerebellum. GlyT2 plays an essential role in clearing glycine from the synaptic cleft, thereby terminating glycinergic neurotransmission. This process is critical for maintaining inhibitory signaling in the central nervous system. Hyperekplexia 3 (OMIM #614618) is a rare neonatal-onset disorder characterized by exaggerated startle responses to unexpected sensory stimuli, muscle stiffness, hypertonia, cyanosis, and apnea, which can be life-threatening in early infancy. Symptoms may improve with age. The gene–disease relationship is supported by genetic evidence from 23 unrelated probands reported across eight publications. This curation includes 28 SLC6A5 variants associated with autosomal recessive inheritance, including missense, nonsense, splicing, frameshift, and in‑frame deletion variants (PMIDs: 16751771, 22700964, 31370103, 16884688, 34266921, 31604777, 35841715, 40725001). Case‑level evidence strongly supports the association and exceeds the maximum score of 12 points. Experimental data further substantiate the gene–disease relationship. Expression studies confirmed high GlyT2 expression in the brainstem and spinal cord, with lower expression in the cerebellum consistent with the clinical neurological features (PMID: 9845349). Biochemical studies established that GlyT2 is a sodium‑ and chloride‑dependent transporter required for regulating glycine levels at inhibitory synapses (PMIDs: 9845349, 14622583). SLC6A5-null mice reproduce key aspects of the human phenotype, including muscle stiffness, spasticity, rigid tone, and prolonged righting times, particularly after handling (PMIDs: 14622583, 22272310).In vitro studies of patient‑derived variants demonstrate reduced glycine transport activity due to impaired membrane localization and decreased protein expression, increased levels of immature protein and ubiquitination‑mediated degradation, and disrupted glycine or sodium binding that alters voltage-dependent responses (PMIDs: 16751771, 22700964, 31370103, 40725001). Notably, the S510R variant has been reported in the heterozygous state without a second SLC6A5 variant in one proband and his reportedly affected parent. Functional studies suggested reduced glycine transporter activity mediated by a dominant-negative mechanism (PMID: 16751771). However, given the limited supporting evidence and the possibility of undetected 2nd variant, the association between SLC6A5 and autosomal dominant hyperekplexia 3 is not currently curated. In summary, there is Definitive evidence supporting the association between SLC6A5 and autosomal recessive hyperekplexia 3, based on robust genetic and experimental findings that have been consistently replicated and upheld over time. This classification was approved by the ClinGen IEM GCEP on February 27, 2026 (SOP Version 12).

Inheritance Pattern: AR

Disease ID:MONDO:0013827

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013827

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013827

Submitter: PanelApp Australia