Submissions for variant NM_003119.4(SPG7):c.2104G>A (p.Glu702Lys)

gnomAD frequency: 0.00001  dbSNP: rs752257333

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200130	SCV000252341	likely pathogenic	not provided	2015-01-29	criteria provided, single submitter	clinical testing	p.Glu702Lys (GAA>AAA): c.2104 G>A in exon 16 of the SPG7 gene (NM_003119.2) A E702K variant that is likely pathogenic was identified in the SPG7 gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The E702K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and most in silico analysis predict this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (S692T, G694D, Q697P) have been reported in association with spastic paraplegia, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in MITONUC-MITOP panel(s).
Invitae	RCV002515440	SCV003295035	uncertain significance	Hereditary spastic paraplegia 7	2023-03-26	criteria provided, single submitter	clinical testing	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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 215224). This variant has not been reported in the literature in individuals affected with SPG7-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 702 of the SPG7 protein (p.Glu702Lys).
PreventionGenetics, part of Exact Sciences	RCV003417715	SCV004107994	uncertain significance	SPG7-related condition	2022-12-28	criteria provided, single submitter	clinical testing	The SPG7 c.2104G>A variant is predicted to result in the amino acid substitution p.Glu702Lys. This variant was reported in study of individuals with suspected mitochondrial disease based on clinical presentation, however additional details were not provided (Table S2, Levy et al. 2021. PubMed ID: 33300680). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89620894-G-A). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.