Submissions for variant NM_014855.3(AP5Z1):c.1072C>T (p.Arg358Cys)

gnomAD frequency: 0.00001  dbSNP: rs551568063

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791496	SCV000930748	uncertain significance	Hereditary spastic paraplegia 48	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 358 of the AP5Z1 protein (p.Arg358Cys). This variant is present in population databases (rs551568063, gnomAD 0.1%). 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: 638840). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt AP5Z1 protein function with a negative predictive value of 80%. 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	RCV000791496	SCV001323057	uncertain significance	Hereditary spastic paraplegia 48	2018-01-12	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV002261204	SCV002542268	uncertain significance	not provided	2021-09-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003338793	SCV004059932	likely benign	Inborn genetic diseases	2023-06-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Neuberg Centre For Genomic Medicine, NCGM	RCV000791496	SCV005329548	uncertain significance	Hereditary spastic paraplegia 48	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense variant c.1072C>T(p.Arg358Cys) in the AP5Z1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.02% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However study of the variant in multiple affected individuals and its functional impact on the protein is required to determine the pathogenicity of the variant. The amino acid Arginine at position 358 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster - Polymorphism) predict no damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.