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: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000650379 SCV000772223 pathogenic Hyperekplexia 3 2024-12-10 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; internal data). ClinVar contains an entry for this variant (Variation ID: 540366). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC6A5 protein function. 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 2024-11-07 criteria provided, single submitter clinical testing Published functional studies demonstrate that p.(F547S) has a negative effect on protein function (PMID: 22700964); 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: 24030948, 29859229, 34266921, 22700964)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000650379 SCV004562738 likely pathogenic Hyperekplexia 3 2024-01-17 criteria provided, single submitter clinical testing The SLC6A5 c.1640T>C; p.Phe547Ser variant (rs772652517, ClinVar Variation ID: 540366) has been reported in the literature 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 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). This variant is also reported in ClinVar (Variation ID: 540366). 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.
PreventionGenetics, part of Exact Sciences RCV004754517 SCV005362607 pathogenic SLC6A5-related disorder 2024-09-24 no assertion criteria provided clinical testing The SLC6A5 c.1640T>C variant is predicted to result in the amino acid substitution p.Phe547Ser. This variant has been reported in the compound heterozygous state in multiple individuals with hyperekplexia (Carta et al. 2012. PubMed ID: 22700964; Thomas et al. 2013. PubMed ID: 24030948; Neupert et al. 2021. PubMed ID: 34266921). This variant has been reported to segregate with hyperekplexia in two different consanguineous families (Internal Data, PreventionGenetics). In vitro functional studies indicate that this variant impacts protein function (Carta et al. 2012. PubMed ID: 22700964) and in silico analyses suggest this variant changes the position of key residues and the binding site resulting in a more severe phenotype (Thomas et al. 2013. PubMed ID: 24030948; Lopez-Corcuera et al. 2019. PubMed ID: 29859229). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.

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