Submissions for variant NM_003119.4(SPG7):c.637C>T (p.Arg213Ter)

gnomAD frequency: 0.00003  dbSNP: rs774774648

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725648	SCV000338358	pathogenic	not provided	2015-12-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000276883	SCV000762587	pathogenic	Hereditary spastic paraplegia 7	2020-02-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SPG7 are known to be pathogenic (PMID: 14722615, 16357941). This variant has been observed in combination with another SPG7 variant in an individual with clinical features of hereditary spastic paraplegia (PMID: 30098094). ClinVar contains an entry for this variant (Variation ID: 285368). This variant is present in population databases (rs774774648, ExAC 0.05%). This sequence change creates a premature translational stop signal (p.Arg213*) in the SPG7 gene. It is expected to result in an absent or disrupted protein product.
GeneDx	RCV000725648	SCV000890847	pathogenic	not provided	2023-12-18	criteria provided, single submitter	clinical testing	Identified in an individual with ataxia who harbored a second pathogenic SPG7 variant (PMID: 30098094); Identified in two individuals with cerebellar atrophy, one of whom was described to harbor a second pathogenic SPG7 variant (PMID: 32161564); Identified in an individual with sporadic amyotrophic lateral sclerosis (PMID: 27790088); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34374492, 35499206, 27790088, 30098094, 32161564, 34507444)
Illumina Laboratory Services, Illumina	RCV000276883	SCV000914743	uncertain significance	Hereditary spastic paraplegia 7	2019-01-11	criteria provided, single submitter	clinical testing	The SPG7 c.637C>T (p.Arg213Ter) variant has been reported in one study and is found in one patient with hereditary spastic paraplegia in a compound heterozygous state (Mancini et al. 2019). Control data are unavailable for this variant, which is reported at a frequency of 0.000462 in the East Asian population of the Exome Aggregation Consortium. Based on the limited clinical evidence and the potential impact of stop-gained variants, the p.Arg213Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive hereditary spastic paraplegia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848059	SCV002105893	pathogenic	Hereditary spastic paraplegia	2020-04-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409411	SCV004116417	pathogenic	SPG7-related disorder	2022-12-15	criteria provided, single submitter	clinical testing	The SPG7 c.637C>T variant is predicted to result in premature protein termination (p.Arg213*). This variant has been documented in both the compound heterozygous and heterozygous states in patients with spastic paraplegia 7 (Patient Table S2 in Mancini et al. 2018. PubMed ID: 30098094; Patient CB_3 and CB_4 in Lupo et al. 2020. PubMed ID: 32161564), and found in the compound heterozygous state in a patient with parkinsonism (Bhattacharjee et al. 2021. PubMed ID: 34507444). This variant was also identified in the heterozygous state in a patient with ALS who also had an additional variant in the GARS gene (Patient 385 in Krüger et al. 2016. PubMed ID: 27790088). This variant is reported in 0.038% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89592755-C-T). Nonsense variants in SPG7 are expected to be pathogenic. This variant is interpreted as pathogenic.
GenomeConnect, ClinGen	RCV000276883	SCV000784708	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.