Submissions for variant NM_014855.3(AP5Z1):c.2287G>A (p.Val763Met)

gnomAD frequency: 0.00013  dbSNP: rs147369435

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468090	SCV000553708	uncertain significance	Hereditary spastic paraplegia 48	2022-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 763 of the AP5Z1 protein (p.Val763Met). This variant is present in population databases (rs147369435, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with AP5Z1-related conditions. ClinVar contains an entry for this variant (Variation ID: 412232). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; 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.
Illumina Laboratory Services, Illumina	RCV000468090	SCV001323320	uncertain significance	Hereditary spastic paraplegia 48	2018-03-30	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114592	SCV003801090	uncertain significance	not specified	2023-01-11	criteria provided, single submitter	clinical testing	Variant summary: KIAA0415 c.2287G>A (p.Val763Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 247596 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2287G>A has been reported in the literature in at-least one individual affected with Hereditary Spastic Paraplegia (example: DAmore_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Spastic Paraplegia 48. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV003480647	SCV004223985	uncertain significance	not provided	2022-04-19	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000468090	SCV004808227	uncertain significance	Hereditary spastic paraplegia 48	2024-03-29	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV003480647	SCV005188419	uncertain significance	not provided		criteria provided, single submitter	not provided
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV003480647	SCV005199547	uncertain significance	not provided	2023-02-08	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV003480647	SCV005621381	uncertain significance	not provided	2023-12-29	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Computational tools disagree on the variant's effect on normal protein function.