ClinVar Miner

Submissions for variant NM_004211.5(SLC6A5):c.1640T>C (p.Phe547Ser)

gnomAD frequency: 0.00001  dbSNP: rs772652517
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Total submissions: 4
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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
GeneDx 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, Molecular Genetics and Genomics, 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.

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