ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs774774648
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Total submissions: 7
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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
Invitae 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 2022-11-29 criteria provided, single submitter clinical testing Identified in an individual with ataxia who harbored a second pathogenic SPG7 variant (Mancini et al., 2018); Identified in two individuals with cerebellar atrophy, one of whom was described to harbor a second pathogenic SPG7 variant (Lupo et al., 2020); Identified in an individual with sporadic amyotrophic lateral sclerosis (Kruger et al., 2016); 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: 27790088, 32161564, 30098094, 34374492, 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 ( 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.

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