Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000650379 | SCV000772223 | pathogenic | Hyperekplexia 3 | 2024-01-17 | criteria provided, single submitter | 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; 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. |
Mendelics | RCV000650379 | SCV001138244 | pathogenic | Hyperekplexia 3 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Gene |
RCV002281121 | SCV002569795 | likely pathogenic | not provided | 2022-03-24 | criteria provided, single submitter | clinical testing | 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) |
ARUP Laboratories, |
RCV000650379 | SCV004562738 | likely pathogenic | Hyperekplexia 3 | 2023-10-13 | criteria provided, single submitter | clinical testing | 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. |