Submissions for variant NM_003119.4(SPG7):c.1861C>T (p.Gln621Ter)

dbSNP: rs769258044

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
3billion	RCV002052061	SCV002318474	likely pathogenic	Hereditary spastic paraplegia 7	2022-03-22	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant.It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV002052061	SCV004035222	likely pathogenic	Hereditary spastic paraplegia 7	2023-09-19	criteria provided, single submitter	clinical testing
Tetreault Lab, University of Montreal Hospital Research Centre (CRCHUM)	RCV003329432	SCV004036151	pathogenic	Spastic ataxia		criteria provided, single submitter	research	Stop-gain/nonsense variant of SPG7 predicted to result in a loss-of-function of the mitochondrial metalloprotease through protein truncation and possibly nonsense-mediated decay (NMD). The allele frequency is near-null (gnomAD AF = 0) but the variant has previously been reported once through ClinVar for Spastic Paraplegia 7. Numerous pathogenic variants are reported downstream of the stopgain. In silico predictions support loss-of-function of the allele (CADD = 39; SIFT = 1.00). The metalloprotease is important for mitochondrial function, which correlates with the mitochondrial-related phenotypes of the associated condition. Causes Spastic ataxia with episodic manifestations in compound heterozygosity with NM_003119.4 c.2228T>C.
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV002052061	SCV005044564	pathogenic	Hereditary spastic paraplegia 7	2022-01-01	criteria provided, single submitter	research
GeneDx	RCV004729059	SCV005332523	pathogenic	not provided	2024-03-09	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33624863)
Solve-RD Consortium	RCV002052061	SCV005091281	likely pathogenic	Hereditary spastic paraplegia 7	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team