Submissions for variant NM_015346.4(ZFYVE26):c.2254C>T (p.Gln752Ter)

dbSNP: rs1057518016

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413277	SCV000491366	likely pathogenic	not provided	2016-01-20	criteria provided, single submitter	clinical testing	The Q752X variant in the ZFYVE26 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q752X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q752X variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001383171	SCV001582236	pathogenic	Spastic paraplegia	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln752*) in the ZFYVE26 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ZFYVE26 are known to be pathogenic (PMID: 18394578, 19805727). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 24833714, 29858556, 30555096). ClinVar contains an entry for this variant (Variation ID: 372839). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000664216	SCV002557618	pathogenic	Hereditary spastic paraplegia 15	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 15 (MIM#270700). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in an individual with spastic paraplegia (PMID: 30555096) and classified as likely pathogenic and pathogenic in ClinVar. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity	RCV000664216	SCV003821888	pathogenic	Hereditary spastic paraplegia 15	2022-11-09	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Cologne University	RCV000664216	SCV000787777	pathogenic	Hereditary spastic paraplegia 15	2018-04-25	no assertion criteria provided	clinical testing
Counsyl	RCV000664216	SCV000792992	pathogenic	Hereditary spastic paraplegia 15	2017-07-25	no assertion criteria provided	clinical testing