Submissions for variant NM_003119.4(SPG7):c.2228T>C (p.Ile743Thr)

gnomAD frequency: 0.00006  dbSNP: rs752623413

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198819	SCV000252332	likely pathogenic	not provided	2020-11-04	criteria provided, single submitter	clinical testing	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: 25681447, 22964162, 27123479, 18799786, 29023604, 27790088, 29482223, 28362824, 30098094, 24727571, 33300680)
Genetic Services Laboratory, University of Chicago	RCV000500664	SCV000597238	pathogenic	Hereditary spastic paraplegia 7	2017-05-17	criteria provided, single submitter	clinical testing
Invitae	RCV000500664	SCV000762593	pathogenic	Hereditary spastic paraplegia 7	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 743 of the SPG7 protein (p.Ile743Thr). This variant is present in population databases (rs752623413, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive primary lateral sclerosis and hereditary spastic paraplegia and adult-onset upper motor neuron syndrome, ataxia, or progressive external ophthalmoplegia (PMID: 18799786, 22964162, 24727571, 25681447, 27123479). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215218). 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%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000198819	SCV001246901	pathogenic	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Paris Brain Institute, Inserm - ICM	RCV000500664	SCV001451068	pathogenic	Hereditary spastic paraplegia 7		criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001640295	SCV001519322	pathogenic	Spastic ataxia	2021-07-12	criteria provided, single submitter	research
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847889	SCV002105877	pathogenic	Hereditary spastic paraplegia	2020-03-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000500664	SCV002579832	likely pathogenic	Hereditary spastic paraplegia 7	2021-12-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000500664	SCV002598747	pathogenic	Hereditary spastic paraplegia 7	2022-09-22	criteria provided, single submitter	clinical testing	Variant summary: SPG7 c.2228T>C (p.Ile743Thr) 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 5.2e-05 in 251340 control chromosomes (gnomAD). c.2228T>C has been reported in the literature in multiple individuals affected with Ataxia/Hereditary Spastic Paraplegia 7 (e.g. van Gassen_2012, Coutelier_2018, Mancini_2019, Bogdanova-Mihaylova_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000500664	SCV002764909	pathogenic	Hereditary spastic paraplegia 7	2021-11-09	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000500664	SCV003922040	likely pathogenic	Hereditary spastic paraplegia 7		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.2228T>C in Exon 17 of the SPG7 gene that results in the amino acid substitution p.Ile743Thr was identified. The observed variant has a minor allele frequency of 0.00005/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as PathogenicLikelyPathogenic(Variant ID 215218). This variant has been previously reported in Pfeffer et al., 2015. Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.
Tetreault Lab, University of Montreal Hospital Research Centre (CRCHUM)	RCV001640295	SCV004036152	pathogenic	Spastic ataxia		criteria provided, single submitter	research	Missense variant of SPG7 predicted that is predicted to disrupt the function of the mitochondrial metalloprotease. The allele frequency is low (gnomAD AF = 4.95e-5) but the variant has previously been reported multiple times (13) through ClinVar for Hereditary Spastic Paraplegia 7, and spastic ataxia. In silico predictions support loss-of-function of the allele (CADD = 25.4; SIFT = 0.99). The metalloprotease is important for mitochondrial function, which correlates with the mitochondrial-related phenotypes of associated condition. Causes Spastic ataxia with episodic manifestations in compound heterozygosity with NM_003119.4 c.1861C>T.
PreventionGenetics, part of Exact Sciences	RCV003401074	SCV004104063	pathogenic	SPG7-related disorder	2023-07-10	criteria provided, single submitter	clinical testing	The SPG7 c.2228T>C variant is predicted to result in the amino acid substitution p.Ile743Thr. This variant has been reported in the compound heterozygous state in multiple individuals with spastic paraplegia, upper motor disease, or ataxia (Brugman et al. 2008. PubMed ID: 18799786; Pfeffer et al. 2015. PubMed ID: 25681447; Coutelier et al. 2018. PubMed ID: 29482223). This variant is reported in 0.0096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89623341-T-C). This variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/215218/). Given the evidence, we interpret c.2228T>C (p.Ile743Thr) as pathogenic for autosomal recessive disease.
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000500664	SCV004171150	pathogenic	Hereditary spastic paraplegia 7		criteria provided, single submitter	not provided
GenomeConnect, ClinGen	RCV000500664	SCV000607223	not provided	Hereditary spastic paraplegia 7		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Genomics England Pilot Project, Genomics England	RCV000500664	SCV001760394	pathogenic	Hereditary spastic paraplegia 7		no assertion criteria provided	clinical testing