Submissions for variant NM_001244008.2(KIF1A):c.1360G>A (p.Ala454Thr)

gnomAD frequency: 0.00001  dbSNP: rs1575598898

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000794027	SCV000933410	uncertain significance	Hereditary spastic paraplegia 30; Neuropathy, hereditary sensory, type 2C; Intellectual disability, autosomal dominant 9	2022-07-06	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. ClinVar contains an entry for this variant (Variation ID: 640897). This variant has not been reported in the literature in individuals affected with KIF1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 445 of the KIF1A protein (p.Ala445Thr).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797796	SCV002041668	uncertain significance	not specified	2021-11-11	criteria provided, single submitter	clinical testing	Variant summary: KIF1A c.1333G>A (p.Ala445Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248238 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1333G>A in individuals affected with NESCAV Syndrome/Hereditary Sensory And Autonomic Neuropathy Type IIC/Spastic paraplegia type 30 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.