Submissions for variant NM_003119.4(SPG7):c.1904C>T (p.Ser635Leu)

dbSNP: rs864622507

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206309	SCV000260894	pathogenic	Hereditary spastic paraplegia 7	2022-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 635 of the SPG7 protein (p.Ser635Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 16534102, 29915382, 30533525, 32002796; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 220393). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000206309	SCV000597236	likely pathogenic	Hereditary spastic paraplegia 7	2015-10-07	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000993072	SCV001145784	uncertain significance	not provided	2019-05-22	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV000993072	SCV001755412	uncertain significance	not provided	2021-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000993072	SCV001992470	uncertain significance	not provided	2024-08-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16534102, 28294470, 30533525, 32002796, 38374194, 22571692, 29915382)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000206309	SCV002051454	pathogenic	Hereditary spastic paraplegia 7	2021-12-03	criteria provided, single submitter	clinical testing	Variant summary: SPG7 c.1904C>T (p.Ser635Leu) results in a non-conservative amino acid change located in the Peptidase M41 domain (IPR000642) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245664 control chromosomes (gnomAD). c.1904C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Hereditary Spastic Paraplegia and cerebellar ataxia (e.g. Elleuch_2006, Hewamadduma_2018, Sun_2019, Mao_2020) and was shown to segregate with disease in at least one family (Mao_2020). 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. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003897449	SCV004717845	likely pathogenic	SPG7-related disorder	2023-10-18	no assertion criteria provided	clinical testing	The SPG7 c.1904C>T variant is predicted to result in the amino acid substitution p.Ser635Leu. This variant has been reported with another SPG7 variant in multiple unrelated individuals with hereditary spastic paraplegia (HSP) and cerebellar ataxia (Elleuch et al. 2006. PubMed ID: 16534102; Hewamadduma et al. 2018. PubMed ID: 30533525; Sun et al. 2018. PubMed ID: 29915382). This variant has also been documented in the homozygous state in two affected siblings; segregation analysis revealed that both unaffected parents were heterozygous carriers for this variant (Mao et al. 2020. PubMed ID: 32002796). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.