Submissions for variant NM_003119.4(SPG7):c.584A>G (p.Tyr195Cys)

gnomAD frequency: 0.00009  dbSNP: rs145776296

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000725649	SCV000252318	uncertain significance	not provided	2017-07-14	criteria provided, single submitter	clinical testing	p.Tyr195Cys (TAC>TGC), c.584 A>G in exon 4 of the SPG7 gene (NM_003119.2). The Y195C missense substitution in the SPG7 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid substitution is semi-conservative in that both Tyrosine and Cysteine are uncharged, polar amino acids; however, the introduction of a Cysteine residue may introduce disulfide bonds in the SPG7 protein and impact the secondary structure of this protein. This change occurs at a position in the SPG7 protein that is not highly conserved. In-silico analyses are not consistent in their predictions as to whether or not Y195C is likely to be damaging to the SPG7 protein. Therefore, based on the currently available information it is unclear whether Y195C is a disease-causing mutation or a rare benign variant. The variant is found in OAPEO-MITOP panel(s).
Eurofins Ntd Llc (ga)	RCV000725649	SCV000338363	uncertain significance	not provided	2015-12-14	criteria provided, single submitter	clinical testing
Invitae	RCV000473038	SCV000552952	uncertain significance	Hereditary spastic paraplegia 7	2023-05-19	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. 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 not expected to disrupt SPG7 protein function. ClinVar contains an entry for this variant (Variation ID: 215205). This variant has not been reported in the literature in individuals affected with SPG7-related conditions. This variant is present in population databases (rs145776296, gnomAD 0.01%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 195 of the SPG7 protein (p.Tyr195Cys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330570	SCV004038761	uncertain significance	not specified	2023-08-21	criteria provided, single submitter	clinical testing	Variant summary: SPG7 c.584A>G (p.Tyr195Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251076 control chromosomes (gnomAD). To our knowledge, no occurrence of c.584A>G in individuals affected with Hereditary Spastic Paraplegia 7 and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.