Submissions for variant NM_014855.3(AP5Z1):c.1964C>T (p.Ser655Leu)

gnomAD frequency: 0.00065  dbSNP: rs61750324

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000462575	SCV000469505	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.
GeneDx	RCV000766950	SCV000532792	uncertain significance	not provided	2020-11-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462575	SCV000553710	uncertain significance	Hereditary spastic paraplegia 48	2022-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 655 of the AP5Z1 protein (p.Ser655Leu). This variant is present in population databases (rs61750324, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 360343). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AP5Z1 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	RCV000433241	SCV000612374	benign	not specified	2020-07-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000766950	SCV001155013	likely benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	AP5Z1: BP4
Mayo Clinic Laboratories, Mayo Clinic	RCV000766950	SCV001714810	uncertain significance	not provided	2023-06-16	criteria provided, single submitter	clinical testing	BS1
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848711	SCV002106165	uncertain significance	Hereditary spastic paraplegia	2017-07-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002523598	SCV003686306	uncertain significance	Inborn genetic diseases	2021-07-09	criteria provided, single submitter	clinical testing	The c.1964C>T (p.S655L) alteration is located in exon 16 (coding exon 16) of the AP5Z1 gene. This alteration results from a C to T substitution at nucleotide position 1964, causing the serine (S) at amino acid position 655 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.