Submissions for variant NM_003119.4(SPG7):c.1672A>T (p.Lys558Ter)

gnomAD frequency: 0.00010  dbSNP: rs369227537

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168257	SCV000218928	pathogenic	Hereditary spastic paraplegia 7	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys558*) 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 (rs369227537, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 22964162, 24727571, 26756429). ClinVar contains an entry for this variant (Variation ID: 188276). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000413970	SCV000490983	pathogenic	not provided	2024-09-20	criteria provided, single submitter	clinical testing	Nonsense 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: 27858775, 29057857, 24727571, 26756429, 22964162, 31589614, 37121968, 28362824, 34983064)
Athena Diagnostics	RCV000413970	SCV000844095	pathogenic	not provided	2022-10-29	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). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000413970	SCV001447168	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Paris Brain Institute, Inserm - ICM	RCV000168257	SCV001451058	pathogenic	Hereditary spastic paraplegia 7		criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847793	SCV002105851	pathogenic	Hereditary spastic paraplegia	2016-12-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000168257	SCV002809816	pathogenic	Hereditary spastic paraplegia 7	2021-10-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002515187	SCV003731671	pathogenic	Inborn genetic diseases	2022-08-17	criteria provided, single submitter	clinical testing	The c.1672A>T (p.K558*) alteration, located in exon 13 (coding exon 13) of the SPG7 gene, consists of a A to T substitution at nucleotide position 1672. This changes the amino acid from a lysine (K) to a stop codon at amino acid position 558. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in the homozygous and compound heterozygous states in multiple individuals with features of SPG7-related spastic paraplegia (Iqbal, 2017; Pfeffer, 2014; Rydning, 2016; Taylor, 2019; van Gassen, 2012). Based on the available evidence, this alteration is classified as pathogenic.
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV000168257	SCV005044591	pathogenic	Hereditary spastic paraplegia 7	2022-01-01	criteria provided, single submitter	research
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000413970	SCV005196851	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000168257	SCV005399560	pathogenic	Hereditary spastic paraplegia 7	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 7 (MIM#607259) and optical atrophy (MONDO:0003608). (I) 0108 - This gene is associated with both recessive and dominant disease. This gene is associated with autosomal recessive spastic paraplegia 7 and autosomal dominant optical atrophy (PMIDs: 31854126, 32548275). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (37 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in compound heterozygous and homozygous individuals with spastic paraplegia. Some of these individuals also had ataxia (ClinVar, PMID: 22964162). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000508922	SCV000575908	pathogenic	Mitochondrial disease	2017-04-07	no assertion criteria provided	clinical testing
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	RCV000168257	SCV000926207	pathogenic	Hereditary spastic paraplegia 7	2019-05-03	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003416049	SCV004118308	pathogenic	SPG7-related disorder	2024-03-14	no assertion criteria provided	clinical testing	The SPG7 c.1672A>T variant is predicted to result in premature protein termination (p.Lys558*). This variant has been reported to be causative for spastic paraplegia (van Gassen et al. 2012. PubMed ID: 22964162; Bhattacharjee et al. 2017. PubMed ID: 29057857). This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in SPG7 are expected to be pathogenic. This variant is interpreted as pathogenic.
GenomeConnect - Brain Gene Registry	RCV000168257	SCV004176874	not provided	Hereditary spastic paraplegia 7		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 11-08-2022 by Children's Hospital of Philadelphia. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.