Submissions for variant NM_015915.5(ATL1):c.1244G>A (p.Arg415Gln)

dbSNP: rs397514712

Total submissions: 4

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000050231	SCV001534565	uncertain significance	Hereditary spastic paraplegia 3A	2021-10-20	criteria provided, single submitter	clinical testing	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: 15184642, 16401858, 19459885, 20932283, 23483706, 24417445, 24451228, 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. 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. ClinVar contains an entry for this variant (Variation ID: 56844). This missense change 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. This variant is not present in population databases (ExAC no frequency). 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.
Athena Diagnostics	RCV000480817	SCV004229185	uncertain significance	not provided	2023-03-28	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one family with clinical features associated with this gene. This variant was identified in the heterozygous state in both affected and asymptomatic members of the family. This variant was also identified in the homozygous state in other affected members of the family. Computational tools disagree on the variant's effect on normal protein function.
OMIM	RCV000050231	SCV000082810	pathogenic	Hereditary spastic paraplegia 3A	2013-06-01	no assertion criteria provided	literature only