Submissions for variant NM_014855.3(AP5Z1):c.1334C>T (p.Pro445Leu)

gnomAD frequency: 0.00006  dbSNP: rs566333309

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000469873	SCV000469486	uncertain significance	Hereditary spastic paraplegia 48	2018-01-13	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469873	SCV000553711	uncertain significance	Hereditary spastic paraplegia 48	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 445 of the AP5Z1 protein (p.Pro445Leu). This variant is present in population databases (rs566333309, gnomAD 0.2%). 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: 360326). 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: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055931	SCV005725878	uncertain significance	not specified	2024-11-29	criteria provided, single submitter	clinical testing	Variant summary: AP5Z1 c.1334C>T (p.Pro445Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 158414 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in AP5Z1 causing Hereditary Spastic Paraplegia 48, allowing no conclusion about variant significance. c.1334C>T has been reported in the literature without strong evidence for or against pathogenicity (example: Wang_2024) . This report does 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. The following publication has been ascertained in the context of this evaluation (PMID: 38292225). ClinVar contains an entry for this variant (Variation ID: 360326). Based on the evidence outlined above, the variant was classified as uncertain significance.