ClinVar Miner

Submissions for variant NM_000334.4(SCN4A):c.2095G>A (p.Ala699Thr)

dbSNP: rs1057518865
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000414860 SCV000492781 pathogenic Myotonia; Handgrip myotonia 2015-10-09 criteria provided, single submitter clinical testing
Athena Diagnostics RCV001566689 SCV000615068 likely pathogenic not provided 2021-10-26 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Computational tools predict that this variant is damaging.
Labcorp Genetics (formerly Invitae), Labcorp RCV001070785 SCV001236055 likely pathogenic Hyperkalemic periodic paralysis 2024-12-23 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 699 of the SCN4A protein (p.Ala699Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paramyotonia congenita (PMID: 27922499, 32660787, 32849172; internal data). ClinVar contains an entry for this variant (Variation ID: 374058). 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 SCN4A protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001070785 SCV001369209 pathogenic Hyperkalemic periodic paralysis 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic.
GeneDx RCV001566689 SCV001790249 uncertain significance not provided 2024-06-24 criteria provided, single submitter clinical testing Observed in multiple individuals with myotonia (Bugiardini et al., 2015 [Abstract]; Leonardis et al., 2008 [Abstract]); Not observed at significant frequency in large population cohorts (gnomAD); 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: 32849172, 32660787, 33573884, 27922499)
Mayo Clinic Laboratories, Mayo Clinic RCV001566689 SCV002520068 likely pathogenic not provided 2021-07-29 criteria provided, single submitter clinical testing PP3, PP4, PM1, PM2, PS4_moderate
Revvity Omics, Revvity RCV001566689 SCV003821293 uncertain significance not provided 2020-09-04 criteria provided, single submitter clinical testing

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