Submissions for variant NM_003119.4(SPG7):c.1231G>A (p.Asp411Asn)

dbSNP: rs745444834

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000490105	SCV000577710	uncertain significance	not provided	2020-01-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27077743)
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001643206	SCV001519203	pathogenic	Hereditary spastic paraplegia 7	2021-01-04	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001643206	SCV002186067	uncertain significance	Hereditary spastic paraplegia 7	2022-08-09	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 27077743). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 411 of the SPG7 protein (p.Asp411Asn). This variant is also known as D412N. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 427079).
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV001643206	SCV005044516	likely pathogenic	Hereditary spastic paraplegia 7	2022-01-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800424	SCV005422122	uncertain significance	not specified	2024-10-25	criteria provided, single submitter	clinical testing	Variant summary: SPG7 c.1231G>A (p.Asp411Asn) results in a conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250558 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1231G>A has been reported in the literature in at least one compound heterozygous individual affected with clinical features of Hereditary Spastic Paraplegia or as a de novo mutation in an unspecified developmental disorder (e.g. Martinuzzi_2016, Galatolo_2021, Kaplanis_2021). These data do not allow any conclusion about variant significance. 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: 34445196, 33057194, 27077743). ClinVar contains an entry for this variant (Variation ID: 427079). Based on the evidence outlined above, the variant was classified as uncertain significance.