ClinVar Miner

Submissions for variant NM_003119.4(SPG7):c.2096dup (p.Met699fs)

gnomAD frequency: 0.00004  dbSNP: rs747503698
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000460135 SCV000552956 pathogenic Hereditary spastic paraplegia 7 2024-09-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Met699Ilefs*4) 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 (rs747503698, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with SPG7-related conditions. ClinVar contains an entry for this variant (Variation ID: 411678). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000489898 SCV000577548 pathogenic not provided 2025-02-05 criteria provided, single submitter clinical testing Frameshift 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: 34758253, 33726816, 37152446, 22571692, 31589614)
Athena Diagnostics RCV000489898 SCV000844100 pathogenic not provided 2018-05-30 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene.
Mayo Clinic Laboratories, Mayo Clinic RCV000489898 SCV001715176 pathogenic not provided 2020-12-09 criteria provided, single submitter clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund RCV000489898 SCV005198344 pathogenic not provided 2023-05-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000460135 SCV005394468 pathogenic Hereditary spastic paraplegia 7 2024-09-13 criteria provided, single submitter clinical testing Variant summary: SPG7 c.2096dupT (p.Met699IlefsX4) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4.4e-05 in 248248 control chromosomes, predominantly at a frequency of 9.9e-05 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in SPG7 causing Hereditary Spastic Paraplegia 7, allowing no conclusion about variant significance. c.2096dupT has been reported in the literature in unspecified individuals undertaking genetic testing, however not all the information was provided for further analysis (Stranneheim_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Spastic Paraplegia 7. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33726816). ClinVar contains an entry for this variant (Variation ID: 411678). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000460135 SCV005642524 pathogenic Hereditary spastic paraplegia 7 2024-03-05 criteria provided, single submitter clinical testing
Genomics England Pilot Project, Genomics England RCV000460135 SCV001760393 pathogenic Hereditary spastic paraplegia 7 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV003902651 SCV004724679 likely pathogenic SPG7-related disorder 2024-01-29 no assertion criteria provided clinical testing The SPG7 c.2096dupT variant is predicted to result in a frameshift and premature protein termination (p.Met699Ilefs*4). This variant has been reported in the literature; however, phenotypes of the individuals carrying this variant were not specified (Stranneheim et al. 2021. PubMed ID: 33726816; 100,000 Genomes Project Pilot Investigators et al. 2021. PubMed ID: 34758253). This variant is reported in 0.0095% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in SPG7 are expected to be pathogenic. This variant is interpreted as likely pathogenic.

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