ClinVar Miner

Submissions for variant NM_001127713.1(ATL1):c.757G>A (p.Val253Ile) (rs864622520)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206078 SCV000260948 pathogenic Hereditary spastic paraplegia 3A 2020-06-12 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 253 of the ATL1 protein (p.Val253Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant has been identified in patients affected with autosomal dominant hereditary spastic paraplegia (PMID: 24604904, 20932283, 20718791, 16401858, 26208798). This variant has also been observed to co-segregate with disease in affected families with incomplete penetrance (PMID: 15596607, 17285536). ClinVar contains an entry for this variant (Variation ID: 220424). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000235294 SCV000293530 likely pathogenic not provided 2016-02-17 criteria provided, single submitter clinical testing The V253I variant has been reported previously segregating in two unrelated families where some family members demonstrated childhood-onset spasticity, some adult-onset spasticity, and others were asymptomatic, indicating variable expressivity and incomplete penetrance (Durr et al., 2004; Klein et al., 2010). The V253I variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species and missense variants at nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014) in association with an ATL1-related disorder, supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000235294 SCV001149211 likely pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000235294 SCV001447890 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Paris Brain Institute,Inserm - ICM RCV000206078 SCV001451211 pathogenic Hereditary spastic paraplegia 3A criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000235294 SCV001716181 likely pathogenic not provided 2019-08-05 criteria provided, single submitter clinical testing PS4_moderate, PM1, PM2

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