Submissions for variant NM_014855.3(AP5Z1):c.2387G>A (p.Arg796Gln)

gnomAD frequency: 0.00022  dbSNP: rs199981070

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457726	SCV000553712	uncertain significance	Hereditary spastic paraplegia 48	2022-07-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 796 of the AP5Z1 protein (p.Arg796Gln). This variant is present in population databases (rs199981070, gnomAD 0.03%). 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: 412234). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Athena Diagnostics	RCV000518104	SCV000612378	uncertain significance	not specified	2017-06-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000457726	SCV001324975	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	RCV001508576	SCV001714813	uncertain significance	not provided	2020-01-30	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848821	SCV002106186	uncertain significance	Hereditary spastic paraplegia	2019-09-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002525623	SCV003690314	uncertain significance	Inborn genetic diseases	2022-12-28	criteria provided, single submitter	clinical testing	The c.2387G>A (p.R796Q) alteration is located in exon 17 (coding exon 17) of the AP5Z1 gene. This alteration results from a G to A substitution at nucleotide position 2387, causing the arginine (R) at amino acid position 796 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.