Submissions for variant NM_003119.4(SPG7):c.233T>A (p.Leu78Ter)

gnomAD frequency: 0.00014  dbSNP: rs121918358

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Neurogenetics of motion laboratory, Montreal Neurological Institute	RCV000007218	SCV000245724	pathogenic	Hereditary spastic paraplegia 7		criteria provided, single submitter	case-control
GeneDx	RCV000200640	SCV000252327	pathogenic	not provided	2022-02-07	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: 25525159, 27084228, 28362824, 29482223, 18200586, 23065789, 22571692, 26626314, 22964162, 25681447, 25976027, 31433872, 31407473, 33300680, 31589614, 33084218, 33624863)
Invitae	RCV000007218	SCV000640076	pathogenic	Hereditary spastic paraplegia 7	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu78*) 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 (rs121918358, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive hereditary spastic paraplegia (PMID: 18200586, 22571692, 24727571). 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: 6816). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000200640	SCV000844104	pathogenic	not provided	2017-12-22	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000007218	SCV000930176	pathogenic	Hereditary spastic paraplegia 7	2020-05-03	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000007218	SCV001149940	pathogenic	Hereditary spastic paraplegia 7	2019-06-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000200640	SCV001246155	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	SPG7: PM3:Very Strong, PVS1, PM2
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000200640	SCV001447026	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Paris Brain Institute, Inserm - ICM	RCV000007218	SCV001451030	pathogenic	Hereditary spastic paraplegia 7		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000007218	SCV001522926	pathogenic	Hereditary spastic paraplegia 7	2020-01-16	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007218	SCV001934454	pathogenic	Hereditary spastic paraplegia 7	2021-02-24	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_003119.4:c.1529C>T.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847594	SCV002105885	pathogenic	Hereditary spastic paraplegia	2021-03-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000007218	SCV002580802	pathogenic	Hereditary spastic paraplegia 7	2023-02-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000007218	SCV002809350	likely pathogenic	Hereditary spastic paraplegia 7	2021-12-20	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000007218	SCV004047753	pathogenic	Hereditary spastic paraplegia 7		criteria provided, single submitter	clinical testing	The stop gained variant c.233T>A (p.Leu78Ter) in SPG7 gene has been observed in the literature in the homozygous state in 5 individuals from 3 families affected with HSP (Sanchez-Ferrero E et.al.,2013). This variant has been reported to the ClinVar database as Pathogenic. The c.233T>A variant is reported with allele frequency 0.04% in gnomAD exomes and novel in 1000 Genomes. The nucleotide change c.233T>A in SPG7 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. Variant s in SPG7 genes are known to have both Autosomal dominant and Autosomal recessive pat t ern of inheritance (OMIM #607259)[1,2]. However, Autosomal dominant inheritance is not report ed for this variant in lit erature yet .
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007218	SCV005062121	pathogenic	Hereditary spastic paraplegia 7	2024-03-01	criteria provided, single submitter	clinical testing	Variant summary: SPG7 c.233T>A (p.Leu78X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00042 in 251260 control chromosomes in the gnomAD database, including 2 homozygotes. c.233T>A has been reported in the literature in multiple homozygous individuals affected with Hereditary Spastic Paraplegia (e.g. Arnoldi_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating enzyme activity in homozygous patient fibroblasts with varied results between patients (e.g. Arnoldi_2008). The most pronounced variant effect results in 30%-50% of normal activity. The following publication has been ascertained in the context of this evaluation (PMID: 18200586). ClinVar contains an entry for this variant (Variation ID: 6816). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000007218	SCV000027414	pathogenic	Hereditary spastic paraplegia 7	2008-04-01	no assertion criteria provided	literature only
Institute of Human Genetics, Cologne University	RCV000664258	SCV000787827	uncertain significance	Proximal spinal muscular atrophy	2018-04-26	no assertion criteria provided	clinical testing