Submissions for variant NM_003119.4(SPG7):c.1727C>G (p.Ser576Trp)

dbSNP: rs151249432

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197553	SCV000252340	uncertain significance	not provided	2024-03-22	criteria provided, single submitter	clinical testing	Identified in a patient with hereditary spastic paraplegia who had a second pathogenic SPG7 variant on the opposite allele, however the phase of these variants was not confirmed by parental segregation studies (PMID: 23812641, 32973427); 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; This variant is associated with the following publications: (PMID: 31325016, 32973427, 22571692, 23812641, 33300680)
CeGaT Center for Human Genetics Tuebingen	RCV000197553	SCV000780549	likely pathogenic	not provided	2019-08-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001233181	SCV001405764	likely pathogenic	Hereditary spastic paraplegia 7	2024-06-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 576 of the SPG7 protein (p.Ser576Trp). This variant is present in population databases (rs151249432, gnomAD 0.002%). This missense change has been observed in individuals with autosomal recessive hereditary spastic paraplegia (PMID: 23812641; Invitae). ClinVar contains an entry for this variant (Variation ID: 215223). 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 with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847891	SCV002105854	uncertain significance	Hereditary spastic paraplegia	2022-01-04	criteria provided, single submitter	clinical testing
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV001233181	SCV005044555	likely pathogenic	Hereditary spastic paraplegia 7	2022-01-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782305	SCV005395267	uncertain significance	not specified	2024-09-20	criteria provided, single submitter	clinical testing	Variant summary: SPG7 c.1727C>G (p.Ser576Trp) results in a non-conservative amino acid change located in the Peptidase M41 domain (IPR000642) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251284 control chromosomes (gnomAD). c.1727C>G has been reported in the literature in individuals affected with features of Hereditary Spastic Paraplegia 7 (e.g. Kumar_2013, Estiar_2021, van den Ameele_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23812641, 33300680, 33883237, 33598982). ClinVar contains an entry for this variant (Variation ID: 215223). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.