Submissions for variant NM_015346.4(ZFYVE26):c.5401G>A (p.Ala1801Thr)

gnomAD frequency: 0.00056  dbSNP: rs138965635

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233385	SCV000290152	uncertain significance	Spastic paraplegia	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1801 of the ZFYVE26 protein (p.Ala1801Thr). This variant is present in population databases (rs138965635, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with ZFYVE26-related conditions. ClinVar contains an entry for this variant (Variation ID: 241050). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001729477	SCV002541210	uncertain significance	not provided	2022-06-24	criteria provided, single submitter	clinical testing	BP4
Fulgent Genetics, Fulgent Genetics	RCV001535771	SCV002789321	uncertain significance	Hereditary spastic paraplegia 15	2021-12-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001535771	SCV003826120	uncertain significance	Hereditary spastic paraplegia 15	2021-04-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526650	SCV005039081	uncertain significance	not specified	2024-03-26	criteria provided, single submitter	clinical testing	Variant summary: ZFYVE26 c.5401G>A (p.Ala1801Thr) 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 0.00038 in 249342 control chromosomes. This frequency does not allow conclusion about variant significance. To our knowledge, no occurrence of c.5401G>A in individuals affected with Hereditary Spastic Paraplegia 15 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 241050). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001729477	SCV005685679	uncertain significance	not provided	2024-07-21	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
GenomeConnect - Invitae Patient Insights Network	RCV001535771	SCV001749916	not provided	Hereditary spastic paraplegia 15		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-16-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001729477	SCV001979410	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001729477	SCV001980067	likely benign	not provided		no assertion criteria provided	clinical testing