Submissions for variant NM_003119.4(SPG7):c.2096dup (p.Met699fs) (rs747503698)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000489898	SCV000844100	pathogenic	not provided	2018-05-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000489898	SCV000577548	pathogenic	not provided	2018-11-27	criteria provided, single submitter	clinical testing	The c.2096dupT pathogenic variant in the SPG7 gene causes a frameshift starting with codon Methionine 699, changes this amino acid to an Isoleucine residue and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Met699IlefsX4. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Furthermore, the c.2096dupT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although this pathogenic variant has not been previously reported to our knowledge, other truncating variants in the SPG7 gene have been reported in association with spastic paraplegia (Stenson et al., 2014). Therefore, c.2096dupT is considered a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina	RCV000460135	SCV000914745	uncertain significance	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.
Invitae	RCV000460135	SCV000552956	pathogenic	Spastic paraplegia 7	2018-11-08	criteria provided, single submitter	clinical testing	This sequence change inserts 1 nucleotide in exon 15 of the SPG7 mRNA (c.2096dupT), causing a frameshift at codon 699. This creates a premature translational stop signal (p.Met699Ilefs*4) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in SPG7 are known to be pathogenic (PMID: 22964162). For these reasons, this variant has been classified as Pathogenic.