Submissions for variant NM_015915.5(ATL1):c.1483C>T (p.Arg495Trp)

gnomAD frequency: 0.00001  dbSNP: rs864622269

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203724	SCV000259914	pathogenic	Hereditary spastic paraplegia 3A	2023-08-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATL1 function (PMID: 17321752, 20816793, 23079343). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATL1 protein function. ClinVar contains an entry for this variant (Variation ID: 219827). This missense change has been observed in individuals with autosomal dominant hereditary spastic paraplegia (PMID: 15596607, 15742100, 17502470, 20718791, 20932283). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 495 of the ATL1 protein (p.Arg495Trp). This variant is present in population databases (no rsID available, gnomAD 0.004%).
GeneDx	RCV000390284	SCV000329929	pathogenic	not provided	2023-06-23	criteria provided, single submitter	clinical testing	Published functional studies suggest a dominant-negative effect on the BMPRII signaling pathway (Zhao et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26208798, 20816793, 23079343, 22266886, 20932283, 16815977, 17321752, 15596607, 26374131, 26671083, 20718791, 24451228, 17502470, 15742100, 31236401, 30780198, 35925862, 31920481, 32322428, 23400676, 35788923, 34788679, 23334294, 36359747)
Ambry Genetics	RCV000624103	SCV000741653	likely pathogenic	Inborn genetic diseases	2016-11-15	criteria provided, single submitter	clinical testing
Paris Brain Institute, Inserm - ICM	RCV000203724	SCV001451217	pathogenic	Hereditary spastic paraplegia 3A		criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000390284	SCV001475555	pathogenic	not provided	2020-07-15	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Found in multiple unrelated patients with expected phenotype for this gene. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Statistically associated with disease in multiple families.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000390284	SCV001480099	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000203724	SCV002059669	pathogenic	Hereditary spastic paraplegia 3A	2019-05-15	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847927	SCV002106231	pathogenic	Hereditary spastic paraplegia	2018-07-01	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000203724	SCV002577554	pathogenic	Hereditary spastic paraplegia 3A	2021-09-14	criteria provided, single submitter	clinical testing	PM1, PM2, PP2, PP3, PP5
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	RCV000203724	SCV003920820	pathogenic	Hereditary spastic paraplegia 3A	2023-04-27	criteria provided, single submitter	research
Inherited Neuropathy Consortium Ii, University Of Miami	RCV000203724	SCV004011944	uncertain significance	Hereditary spastic paraplegia 3A	2016-01-06	no assertion criteria provided	literature only