ClinVar Miner

Submissions for variant NM_004321.7(KIF1A):c.4726G>A (p.Val1576Ile) (rs757070178)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489290 SCV000577588 uncertain significance not provided 2016-11-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KIF1A gene. The V1576I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V1576I variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. However, the V1576I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Additionally, 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). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000700081 SCV000828821 uncertain significance Spastic paraplegia 30, autosomal recessive; Hereditary sensory and autonomic neuropathy type IIC; Mental retardation, autosomal dominant 9 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1576 of the KIF1A protein (p.Val1576Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs757070178, ExAC 0.02%). This variant has not been reported in the literature in individuals with KIF1A-related disease. ClinVar contains an entry for this variant (Variation ID: 426987). 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, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000764390 SCV000895443 uncertain significance Hereditary sensory and autonomic neuropathy type IIA; Spastic paraplegia 30, autosomal recessive; Hereditary sensory and autonomic neuropathy type IIC; Mental retardation, autosomal dominant 9 2018-10-31 criteria provided, single submitter clinical testing

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