ClinVar Miner

Submissions for variant NM_004321.7(KIF1A):c.4865C>T (p.Ala1622Val) (rs199804623)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000725080 SCV000885635 uncertain significance not provided 2018-01-12 criteria provided, single submitter clinical testing The KIF1A c.4865C>T; p.Ala1622Val variant (rs199804623), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European population frequency of 0.04% (identified on 52 out of 126,068 chromosomes). The alanine at position 1622 is weakly conserved, considering 13 species, and computational analyses of the effects of the p.Ala1622Val variant on protein structure and function make conflicting predictions (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Ala1622Val variant cannot be determined with certainty.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725080 SCV000333838 uncertain significance not provided 2016-11-30 criteria provided, single submitter clinical testing
GeneDx RCV000725080 SCV000574254 uncertain significance not provided 2017-03-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KIF1A gene. The A1622V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A1622V variant is observed in 6/16480 (0.04 %) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A1622V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. This amino acid substitution does not occur within the predicted motor domain of the protein, where all pathogenic missense KIF1A pathogenic variants have been identified to-date (Lee et al., 2014). However, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000282862 SCV000429166 uncertain significance Spastic Paraplegia, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000347179 SCV000429167 uncertain significance Hereditary sensory and autonomic neuropathy type II 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000382915 SCV000429168 uncertain significance Intellectual Disability, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000547693 SCV000638635 uncertain significance Spastic paraplegia 30, autosomal recessive; Hereditary sensory and autonomic neuropathy type IIC; Mental retardation, autosomal dominant 9 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1622 of the KIF1A protein (p.Ala1622Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs199804623, ExAC 0.04%). This variant has not been reported in the literature in individuals with a KIF1A-related disease. ClinVar contains an entry for this variant (Variation ID: 282386). 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: "Benign"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on KIF1A function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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