ClinVar Miner

Submissions for variant NM_001127713.1(ATL1):c.1244G>A (p.Arg415Gln) (rs397514712)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480817 SCV000568782 likely pathogenic not provided 2017-03-21 criteria provided, single submitter clinical testing The R415Q variant in the ATL1 gene has been reported previously in multiple individuals in a family affected with hereditary spastic paraplegia in both the homozygous and heterozygous state (Varga et al., 2013). The R415Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R415Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The R415Q variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000050231 SCV001534565 uncertain significance Hereditary spastic paraplegia 3A 2020-09-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 415 of the ATL1 protein (p.Arg415Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal dominant and autosomal recessive hereditary spastic paraplegia (PMID: 23483706). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 56844). 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 not expected to disrupt ATL1 protein function. This variant disrupts the p.Arg415 amino acid residue in ATL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20932283, 24451228, 19459885, 16401858, 15184642, 24417445, 23483706, 26671083). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000050231 SCV000082810 pathogenic Hereditary spastic paraplegia 3A 2013-06-01 no assertion criteria provided literature only

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