ClinVar Miner

Submissions for variant NM_001127713.1(ATL1):c.715C>T (p.Arg239Cys) (rs119476046)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000004594 SCV000259322 pathogenic Hereditary spastic paraplegia 3A 2020-03-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 239 of the ATL1 protein (p.Arg239Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the heterozygous state in many individuals and families affected with hereditary spastic paraplegia (HSP) and has strong evidence of co-segregation with HSP (PMID: 14607301, 19652243, 25637064, 15517445). ClinVar contains an entry for this variant (Variation ID: 4346). Experimental studies have shown that this missense change impairs the function and intracellular trafficking of the ATL1 protein (PMID: 16537571, 20816793, 23079343). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000215830 SCV000279438 pathogenic not provided 2018-07-26 criteria provided, single submitter clinical testing The R239C pathogenic variant in ATL1 has been reported in multiple individuals with early onsetspastic paraplegia (Stenson et al., 2014). Functional studies indicate that R239C causes proteinsequestration in the Golgi complex (Botzolakis et al., 2011). The R239C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Athena Diagnostics Inc RCV000215830 SCV000612432 pathogenic not provided 2015-12-31 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000004594 SCV000803456 pathogenic Hereditary spastic paraplegia 3A 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Pathogenic, for Spastic paraplegia 3, autosomal dominant, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP1-Strong => PP1 upgraded in strength to Strong (PMID:14607301) (PMID:11685207). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation in independent families (PMID:20932283,11685207,20718791,14607301). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:17321752).
Baylor Genetics RCV000850530 SCV000992739 pathogenic Hereditary spastic paraplegia 3A; Hereditary sensory neuropathy type 1D 2017-12-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000215830 SCV001149210 likely pathogenic not provided 2018-04-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000004594 SCV001362053 pathogenic Hereditary spastic paraplegia 3A 2019-12-24 criteria provided, single submitter clinical testing Variant summary: ATL1 c.715C>T (p.Arg239Cys) results in a non-conservative amino acid change located in the Guanylate-binding domain, N-terminal (IPR015894) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251004 control chromosomes. c.715C>T has been reported in the literature in multiple individuals affected with Spastic paraplegia 3 (Zhao_2001, Novarino_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity as evidenced by a disruption in BMPRII trafficking to the cell surface cell surface (example, Zhao_2013). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000215830 SCV001446549 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Paris Brain Institute,Inserm - ICM RCV000004594 SCV001451208 pathogenic Hereditary spastic paraplegia 3A criteria provided, single submitter clinical testing
OMIM RCV000004594 SCV000024768 pathogenic Hereditary spastic paraplegia 3A 2006-05-01 no assertion criteria provided literature only
GeneReviews RCV000004594 SCV000041295 pathologic Hereditary spastic paraplegia 3A 2010-09-21 no assertion criteria provided curation Converted during submission to Pathogenic.
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000004594 SCV001132816 pathogenic Hereditary spastic paraplegia 3A 2019-01-29 no assertion criteria provided clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003978 SCV001162004 pathogenic Spastic paraplegia no assertion criteria provided research

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