Submissions for variant NM_014855.3(AP5Z1):c.1573A>C (p.Lys525Gln)

dbSNP: rs186003800

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476354	SCV000553709	uncertain significance	Hereditary spastic paraplegia 48	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 525 of the AP5Z1 protein (p.Lys525Gln). This variant is present in population databases (rs186003800, gnomAD 0.09%), 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: 412233). 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) performed at Invitae 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.
Fulgent Genetics, Fulgent Genetics	RCV000476354	SCV000895852	uncertain significance	Hereditary spastic paraplegia 48	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000476354	SCV001321670	uncertain significance	Hereditary spastic paraplegia 48	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Paris Brain Institute, Inserm - ICM	RCV000476354	SCV001451121	likely benign	Hereditary spastic paraplegia 48	2023-12-13	criteria provided, single submitter	clinical testing	Individual has a causal pathogenic homozygous variant in RNASEH2B c.529G>A (p.Ala177Thr)
Baylor Genetics	RCV000476354	SCV001524063	uncertain significance	Hereditary spastic paraplegia 48	2020-06-03	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV001508573	SCV001714808	uncertain significance	not provided	2020-06-16	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848820	SCV002106145	uncertain significance	Hereditary spastic paraplegia	2016-12-12	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000476354	SCV002766825	uncertain significance	Hereditary spastic paraplegia 48	2019-08-28	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_014855.3(AP5Z1):c.1573A>C, has been identified in exon 0 of the AP5Z1 gene. The variant is predicted to result in a minor amino acid change from lysine to glutamine at position 525 of the protein (NP_055670.1(AP5Z1):p.(Lys525Gln)). The lysine residue at this position has low conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions for this variant are consistently benign (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.06% (156 hetereozygotes, 0 homozygotes). The variant has been previously described as a Variant of Uncertain Significance (ClinVar). Based on the information available at the time of curation, this variant has been classified as VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525935	SCV005040137	uncertain significance	not specified	2024-03-06	criteria provided, single submitter	clinical testing	Variant summary: KIAA0415 c.1573A>C (p.Lys525Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00064 in 243546 control chromosomes. c.1573A>C has been reported in the literature in individuals affected with Hereditary Spastic Paraplegia without strong evidence of causality (e.g. Slabicki_2010, Mereaux_2022). These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 20613862, 34983064). ClinVar contains an entry for this variant (Variation ID: 412233). Based on the evidence outlined above, the variant was classified as uncertain significance.
Athena Diagnostics	RCV004525935	SCV005621805	likely benign	not specified	2024-11-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816679	SCV005072785	uncertain significance	Retinal dystrophy	2022-01-01	no assertion criteria provided	clinical testing