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

gnomAD frequency: 0.00004  dbSNP: rs747503698

Total submissions: 9

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.