Submissions for variant NM_003119.4(SPG7):c.1447C>T (p.Gln483Ter)

gnomAD frequency: 0.00004  dbSNP: rs562890289

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000420140	SCV000533194	likely pathogenic	not provided	2016-11-01	criteria provided, single submitter	clinical testing	The Q483X variant in the SPG7 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 Q483X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret Q483X as a likely pathogenic variant.
Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	RCV000515851	SCV000574454	pathogenic	Hereditary spastic paraplegia	2017-03-07	criteria provided, single submitter	research
Invitae	RCV001865382	SCV002189599	pathogenic	Hereditary spastic paraplegia 7	2021-11-19	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs562890289, gnomAD 0.02%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 390378). This premature translational stop signal has been observed in individual(s) with clinical features of SPG7-related conditions (PMID: 28832565, 33841295). This sequence change creates a premature translational stop signal (p.Gln483*) in the SPG7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG7 are known to be pathogenic (PMID: 21623769, 22964162).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001865382	SCV004020913	pathogenic	Hereditary spastic paraplegia 7	2023-06-13	criteria provided, single submitter	clinical testing	Variant summary: SPG7 c.1447C>T (p.Gln483X) results in a premature termination codon, predicted to cause an absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant allele was found at a frequency of 1.2e-05 in 251214 control chromosomes (gnomAD). c.1447C>T has been reported in the literature in individuals affected with Hereditary Spastic Paraplegia 7 (e.g. Morais_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28832565). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.