Submissions for variant NM_003119.4(SPG7):c.2084T>C (p.Leu695Pro)

gnomAD frequency: 0.00001  dbSNP: rs864622094

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205117	SCV000259318	pathogenic	Hereditary spastic paraplegia 7	2022-04-20	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 219448). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 695 of the SPG7 protein (p.Leu695Pro). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with primary lateral sclerosis and spasticity, and spastic ataxia (PMID: 27123479, 29482223). 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. 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. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000413637	SCV000491100	likely pathogenic	not provided	2023-09-16	criteria provided, single submitter	clinical testing	Observed with a second pathogenic variant in patients in published literature, although phase of the two variants was not confirmed (Coutelier et al., 2018; Bogdanova-Mihaylova et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27123479, 22571692, 29482223, 32816195)
Athena Diagnostics Inc	RCV000413637	SCV000615435	pathogenic	not provided	2017-07-31	criteria provided, single submitter	clinical testing
Paris Brain Institute, Inserm - ICM	RCV000205117	SCV001451066	pathogenic	Hereditary spastic paraplegia 7		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000413637	SCV002563368	likely pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing