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

gnomAD frequency: 0.00004  dbSNP: rs747503698

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000460135	SCV000552956	pathogenic	Hereditary spastic paraplegia 7	2023-11-24	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	2022-08-12	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)
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.
Illumina Laboratory Services, Illumina	RCV000460135	SCV000914745	uncertain significance	Hereditary spastic paraplegia 7	2018-10-11	criteria provided, single submitter	clinical testing	This variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.
Mayo Clinic Laboratories, Mayo Clinic	RCV000489898	SCV001715176	pathogenic	not provided	2020-12-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003902651	SCV004724679	likely pathogenic	SPG7-related disorder	2024-01-29	criteria provided, single submitter	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.
Genomics England Pilot Project, Genomics England	RCV000460135	SCV001760393	pathogenic	Hereditary spastic paraplegia 7		no assertion criteria provided	clinical testing