ClinVar Miner

Submissions for variant NM_004321.7(KIF1A):c.946C>T (p.Arg316Trp) (rs672601370)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624110 SCV000742252 pathogenic Inborn genetic diseases 2017-02-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
Baylor Genetics RCV000850514 SCV000992718 pathogenic Spastic paraplegia 30, autosomal recessive; Hereditary sensory and autonomic neuropathy type IIC; Mental retardation, autosomal dominant 9 2018-10-12 criteria provided, single submitter clinical testing
CHU Sainte-Justine Research Center,University of Montreal RCV000149482 SCV000196127 likely pathogenic Mental retardation, autosomal dominant 9 2014-01-01 no assertion criteria provided clinical testing
GeneDx RCV000374842 SCV000329651 pathogenic not provided 2017-12-04 criteria provided, single submitter clinical testing The R316W pathogenic variant in the KIF1A gene has been reported previously as a de novo change in a 10-year-old female with mild intellectual disability, ataxia, optic nerve atrophy, cerebellar atrophy, neuropathy, and spastic paraparesis (Lee et al., 2015). The R316W variant has also been reported as a de novo variant in a male with cerebellar ataxia, intellectual disability, spasticity, optic atrophy, epilepsy, and cerebral atrophy (Ohba et al., 2015). The R316W variant is not observed in large population cohorts (Lek et al., 2016). The R316W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This amino acid substitution does occur within the predicted motor domain of the protein, where all pathogenic missense KIF1A pathogenic variants have been identified to-date (Lee et al., 2015). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
GenomeConnect, ClinGen RCV000149482 SCV000607365 not provided Mental retardation, autosomal dominant 9 no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000149482 SCV000265578 pathogenic Mental retardation, autosomal dominant 9 2016-02-11 criteria provided, single submitter research
Invitae RCV000149482 SCV000651707 pathogenic Mental retardation, autosomal dominant 9 2017-02-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 316 of the KIF1A protein (p.Arg316Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant has been shown to arise de novo in multiple individuals affected with spastic paraparesis, developmental delay, optic nerve atrophy and various other neurological deficits (PMID: 26354034, 26125038, 25265257). ClinVar contains an entry for this variant (Variation ID: 162060). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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