ClinVar Miner

Submissions for variant NM_003119.4(SPG7):c.679C>T (p.Arg227Ter)

gnomAD frequency: 0.00001  dbSNP: rs764791523
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000276524 SCV000330502 pathogenic not provided 2016-05-06 criteria provided, single submitter clinical testing The R227X pathogenic variant in the SPG7 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R227X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R227X as a pathogenic variant.
Paris Brain Institute, Inserm - ICM RCV001391423 SCV001451032 pathogenic Hereditary spastic paraplegia 7 criteria provided, single submitter clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris RCV001391423 SCV001519204 pathogenic Hereditary spastic paraplegia 7 2021-01-04 criteria provided, single submitter research
Ambry Genetics RCV002519056 SCV003560059 pathogenic Inborn genetic diseases 2022-11-02 criteria provided, single submitter clinical testing The c.679C>T (p.R227*) alteration, located in exon 5 (coding exon 5) of the SPG7 gene, consists of a C to T substitution at nucleotide position 679. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 227. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.002% (4/251496) total alleles studied. The highest observed frequency was 0.007% (2/30616) of South Asian alleles. This variant has been reported in conjunction with a second SPG7 variant in an individual with spastic paraplegia; however, the phase of the two variants was not specified (Martinuzzi, 2016; Galatolo, 2021). Based on the available evidence, this alteration is classified as pathogenic.
Invitae RCV001391423 SCV004296433 pathogenic Hereditary spastic paraplegia 7 2023-02-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg227*) in the SPG7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG7 are known to be pathogenic (PMID: 21623769, 22964162). This variant is present in population databases (rs764791523, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 27077743). ClinVar contains an entry for this variant (Variation ID: 280575). For these reasons, this variant has been classified as Pathogenic.

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