ClinVar Miner

Submissions for variant NM_004984.4(KIF5A):c.484C>T (p.Arg162Trp)

dbSNP: rs748551786
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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 RCV001215426 SCV001387171 pathogenic Spastic paraplegia 2023-08-03 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 944917). For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae 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 KIF5A protein function. This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 25352184, 27084214, 30778698). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs748551786, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 162 of the KIF5A protein (p.Arg162Trp).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001268563 SCV001447570 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Institute of Human Genetics, University Hospital of Duesseldorf RCV003336339 SCV004046789 pathogenic Hereditary spastic paraplegia 10 criteria provided, single submitter not provided
PreventionGenetics, part of Exact Sciences RCV004548072 SCV004113681 likely pathogenic KIF5A-related disorder 2023-07-27 criteria provided, single submitter clinical testing The KIF5A c.484C>T variant is predicted to result in the amino acid substitution p.Arg162Trp. This variant was reported in an individuals with hereditary spastic paraplegia and in at least one study segregate extensively with disease in a family (Supplementary Figure 2, Carosi et al 2015. PubMed ID: 25352184; Elert-Dobkowska et al. 2019. PubMed ID: 30778698). However in a different family, the variant was observed in unaffected individuals with different phenotypes than the initial report, indicating interfamilial phenotypic variability (Kaji et al. 2016. PubMed ID: 27084214). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-57958739-C-T). We interpret this variant as likely pathogenic.
GeneDx RCV001268563 SCV005324982 likely pathogenic not provided 2023-11-15 criteria provided, single submitter clinical testing 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: 27084214, 30778698, 33272564, 25352184)

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