Submissions for variant NM_003119.4(SPG7):c.1996G>C (p.Gly666Arg)

gnomAD frequency: 0.00001  dbSNP: rs752989523

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200425	SCV000254783	pathogenic	Hereditary spastic paraplegia 7	2022-10-13	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs752989523, gnomAD 0.002%). For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt SPG7 protein function. ClinVar contains an entry for this variant (Variation ID: 216571). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 23733235; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 666 of the SPG7 protein (p.Gly666Arg).
GeneDx	RCV001562435	SCV001785195	likely pathogenic	not provided	2023-04-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported previously, along with a second variant, in individuals with spastic paraplegia (Yoon et al., 2013).; This variant is associated with the following publications: (PMID: 23733235, 22571692)
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV000200425	SCV005044526	pathogenic	Hereditary spastic paraplegia 7	2022-01-01	criteria provided, single submitter	research
Genetic Services Laboratory, University of Chicago	RCV001562435	SCV003840078	likely pathogenic	not provided	2022-09-25	no assertion criteria provided	clinical testing	DNA sequence analysis of the SPG7 gene demonstrated a sequence change, c.1996G>C, in exon 15 that results in an amino acid change, p.Gly666Arg. The p.Gly666Arg change affects a highly conserved amino acid residue located in a domain of the SPG7 protein that is known to be functional. The p.Gly666Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This particular amino acid change has been described in the literature in trans with a pathogenic variant in two individuals with spastic paraplegia (PMID: 23733235). This sequence change has been described in the gnomAD database with a frequency of 0.0008% in the overall population (dbSNP rs752989523). These collective evidences indicate that this sequence change is likely pathogenic.