ClinVar Miner

Submissions for variant NM_015915.5(ATL1):c.1247G>A (p.Arg416His)

gnomAD frequency: 0.00001  dbSNP: rs1395551564
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001064153 SCV001229035 uncertain significance Hereditary spastic paraplegia 3A 2021-10-28 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg416 amino acid residue in ATL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21336785, 22581552, 29980238). 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. ClinVar contains an entry for this variant (Variation ID: 858305). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 416 of the ATL1 protein (p.Arg416His). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 19768483).
GeneDx RCV001593242 SCV001824680 likely pathogenic not provided 2019-01-02 criteria provided, single submitter clinical testing Reported in an adult female with HSP, with additional findings of cerebellar involvement; it was also identified in her father with an ALS-like phenotype (de Leva et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19768483)
Ambry Genetics RCV002393313 SCV002672769 uncertain significance Inborn genetic diseases 2019-12-27 criteria provided, single submitter clinical testing The p.R416H variant (also known as c.1247G>A), located in coding exon 12 of the ATL1 gene, results from a G to A substitution at nucleotide position 1247. The arginine at codon 416 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in an Italian family with a complex phenotype, consisting of hereditary spastic paraplegia with cerebellar involvement presentation in the proband and an amyotrophic lateral sclerosis-like phenotype in her father (de Leva MF et al. J. Neurol., 2010 Mar;257:328-31). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. .
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001593242 SCV004565248 uncertain significance not provided 2023-02-21 criteria provided, single submitter clinical testing The ATL1 c.1247G>A; p.Arg416His variant (rs1395551564) is reported in an individual with hereditary spastic paraplegia with cerebellar involvement and in the patient's father who had an amyotrophic lateral sclerosis-like syndrome (de Leva 2010). This variant is also reported in ClinVar (Variation ID: 858305). It is only found on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.631). Due to limited information, the clinical significance of this variant is uncertain at this time. References: de Leva MF et al. Complex phenotype in an Italian family with a novel mutation in SPG3A. J Neurol. 2010 Mar;257(3):328-31. PMID: 19768483.
Inherited Neuropathy Consortium Ii, University Of Miami RCV001064153 SCV004011939 uncertain significance Hereditary spastic paraplegia 3A 2016-01-06 no assertion criteria provided literature only

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