Submissions for variant NM_003119.3(SPG7):c.1454_1462delGGCGGGAGA (p.Arg485_Glu487del)

dbSNP: rs768823392

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000475192	SCV000552958	pathogenic	Hereditary spastic paraplegia 7	2023-11-24	criteria provided, single submitter	clinical testing	This variant, c.1454_1462del, results in the deletion of 3 amino acid(s) of the SPG7 protein (p.Arg485_Glu487del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs768823392, gnomAD 0.08%). This variant has been observed in individual(s) with hereditary spastic paraplegia (PMID: 11222789, 22964162, 23065789, 23269439, 23812641, 24466038, 24727571, 26756429, 27165006). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 411680). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000479409	SCV000566111	pathogenic	not provided	2017-10-17	criteria provided, single submitter	clinical testing	The c.1454_1462delGGCGGGAGA (also reported as c.1450_1458del due to alternativenomenclature) in the SPG7 gene has been reported previously in association with spastic paraplegia. Most affectedindividuals were homozygous or compound heterozyogous for SPG7 variants and had typical features of spasticparaplegia 7 (McDermott et al., 2001; van Gassen et al., 2012; Klebe et al., 2012). When reported in theheterozygous state, some individuals had a later onset and milder presentation, sometimes with a cerebellar phenotypewithout spasticity (McDermott et al., 2001; Klebe et al., 2012). The c.1454_1462delGGCGGGAGA variant resultsin an in-frame deletion of three amino acid residues from the resulting protein starting with codon Arginine 485 andending with codon Glutamine 487, denoted p.Arg485_Glu487del. The c.1454_1462delGGCGGGAGA variant wasobserved in approximately 0.15% (12/8254 alleles) in individuals of European ancestry in the NHLBI ExomeSequencing Project. Therefore, we interpret c.1454_1462delGGCGGGAGA variant as a pathogenic variant.
Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	RCV000516115	SCV000574448	pathogenic	Hereditary spastic paraplegia	2017-03-07	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000479409	SCV000608793	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	SPG7: PS1, PS4, PM2
Ambry Genetics	RCV000622361	SCV000741674	pathogenic	Inborn genetic diseases	2016-07-18	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626835	SCV000747538	pathogenic	Dysarthria; Gait ataxia; Cerebral cortical atrophy; Spastic paraparesis	2017-01-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626836	SCV000747539	pathogenic	Seizure; Memory impairment; Gait ataxia; Spastic paraplegia	2017-01-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000475192	SCV000809094	pathogenic	Hereditary spastic paraplegia 7	2018-06-13	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000475192	SCV001149941	pathogenic	Hereditary spastic paraplegia 7	2019-06-11	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000475192	SCV001428974	pathogenic	Hereditary spastic paraplegia 7	2021-09-13	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000479409	SCV001448087	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Paris Brain Institute, Inserm - ICM	RCV000475192	SCV001451047	pathogenic	Hereditary spastic paraplegia 7		criteria provided, single submitter	clinical testing
Paris Brain Institute, Inserm - ICM	RCV000475192	SCV001451048	pathogenic	Hereditary spastic paraplegia 7		criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000516115	SCV001652952	pathogenic	Hereditary spastic paraplegia	2020-06-26	criteria provided, single submitter	clinical testing	The p.Arg485_Glu487 del variant in SPG7 is a common pathogenic variant in spastic paraplegia type 7 and it has been reported in the homozygous or compound heterozygous state with another SPG7 pathogenic variant in over 20 individuals with spastic paraplegia (McDermott 2001 PMID: 11222789, van Gassen 2012 PMID: 22964162, Klebe 2012 PMID: 23065789, Pfeffer 2014 PMID: 24727571, van de Warrenburg 2016 PMID: 27165006, Gass 2017 PMID: 29026558, Hewamadduma 2018 PMID: 30533525, Sun 2019 PMID: 29915382, Ngo 2019 PMID: 31692161). This variant also segregated with disease in 4 affected relatives from 4 families (van Gassen PMID: 22964162). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 411680) and has been identified in 0.08% (20/25116) of Finnish chromosomes and 0.04% (55/129114) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is a deletion of 3 amino acids at position 485 and is not predicted to alter the protein reading-frame. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive spastic paraplegia type 7. ACMG/AMP Criteria applied: PM3_VeryStrong, PM4, PP1_Strong.
Athena Diagnostics	RCV000479409	SCV001879860	pathogenic	not provided	2020-09-21	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as c.1450_1458del or c.1450-1_1457del. Pathogenic variants in the SPG7 gene classically exhibit an autosomal recessive mode of disease inheritance, however there is also evidence for autosomal dominant transmission in some families. Consistent with this, some individuals carrying this variant in the heterozygous state display a late onset and/or mild disease (PMID: 11222789, 23065789, 31068484). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. The variant is located in a region that is considered important for protein function and/or structure.
Centogene AG - the Rare Disease Company	RCV000475192	SCV002059503	pathogenic	Hereditary spastic paraplegia 7	2020-06-26	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000516115	SCV002105672	pathogenic	Hereditary spastic paraplegia	2018-07-01	criteria provided, single submitter	clinical testing
3billion	RCV000475192	SCV002573165	pathogenic	Hereditary spastic paraplegia 7	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.028%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant is in trans with the other pathogenic variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000411680 / PMID: 11222789 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000475192	SCV002574834	pathogenic	Hereditary spastic paraplegia 7	2022-09-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000475192	SCV002801973	pathogenic	Hereditary spastic paraplegia 7	2022-02-05	criteria provided, single submitter	clinical testing
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	RCV000475192	SCV003920837	pathogenic	Hereditary spastic paraplegia 7	2023-04-27	criteria provided, single submitter	research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000475192	SCV004035178	pathogenic	Hereditary spastic paraplegia 7	2023-08-25	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000475192	SCV004813963	pathogenic	Hereditary spastic paraplegia 7	2024-02-02	criteria provided, single submitter	clinical testing	Variant summary: SPG7 c.1454_1462delGGCGGGAGA (p.Arg485_Glu487del, also known as c.1450-1_1457del) results in an in-frame deletion that is predicted to remove 3 amino acids from the encoded protein. The variant allele was found at a frequency of 0.00026 in 251444 control chromosomes. c.1454_1462delGGCGGGAGA has been reported in the literature as a common pathogenic variant in multiple individuals affected with Hereditary Spastic Paraplegia 7 (example, Burguez_2017, van Gassen_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29246610, 22964162). ClinVar contains an entry for this variant (Variation ID: 411680). Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, Cologne University	RCV000664257	SCV000787826	uncertain significance	Distal spinal muscular atrophy	2018-04-26	no assertion criteria provided	clinical testing
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	RCV000475192	SCV000926206	pathogenic	Hereditary spastic paraplegia 7	2019-05-03	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000479409	SCV001744268	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000479409	SCV001965290	pathogenic	not provided		no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000475192	SCV002064524	likely pathogenic	Hereditary spastic paraplegia 7	2020-12-15	no assertion criteria provided	clinical testing	DNA sequence analysis of the SPG7 gene demonstrated a nine-base pair deletion in exon 11, c.1454_1462del. This in-frame deletion is predicted to result in the deletion of three amino acid residues, p.Arg485_Glu487del. This in-frame deletion has been described in the homozygous and compound heterozygous states in patients with spastic paraplegia 7 or ataxia (PMIDs: 22964162, 23065789, 11222789). It has been described in the gnomAD population database with a global allele frequency of 0.028% and in the Finnish European subgroup with an allele frequency of 0.080% (rs768823392). Collectively this evidence suggests that this p.Arg485_Glu487del variant is likely pathogenic, however functional studies have not been performed to prove this conclusively
GeneReviews	RCV000475192	SCV004034076	not provided	Hereditary spastic paraplegia 7		no assertion provided	literature only