Submissions for variant NM_003119.4(SPG7):c.1730G>C (p.Gly577Ala)

dbSNP: rs1329063851

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848232	SCV002105856	uncertain significance	Hereditary spastic paraplegia	2018-10-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001885410	SCV002109882	likely pathogenic	Hereditary spastic paraplegia 7	2021-10-16	criteria provided, single submitter	clinical testing	This variant disrupts the p.Gly577 amino acid residue in SPG7. Other variant(s) that disrupt this residue have been observed in individuals with SPG7-related conditions (PMID: 14985266, 21623769), which suggests that this may be a clinically significant amino acid residue. 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. 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. This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 577 of the SPG7 protein (p.Gly577Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331216	SCV004038953	uncertain significance	not specified	2023-08-10	criteria provided, single submitter	clinical testing	Variant summary: SPG7 c.1730G>C (p.Gly577Ala) results in a non-conservative amino acid change located in the Peptidase M41 (IPR000642) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251290 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1730G>C in individuals affected with Hereditary Spastic Paraplegia 7 and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.