ClinVar Miner

Submissions for variant NM_001127713.1(ATL1):c.322A>G (p.Thr108Ala) (rs112496709)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000435741 SCV000512127 uncertain significance not specified 2016-11-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ATL1 gene. The T108A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T108A variant was observed on 30/66,680 (0.04%) alleles from individuals of European background in the Exome Aggregation Consortium (ExAC) data set, indicating it may be a rare benign variant in this population. The T108A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Threonine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000647937 SCV000769744 uncertain significance Hereditary spastic paraplegia 3A 2019-04-23 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 108 of the ATL1 protein (p.Thr108Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs112496709, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with ATL1-related disease. ClinVar contains an entry for this variant (Variation ID: 377500). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Illumina Clinical Services Laboratory,Illumina RCV000647937 SCV001266996 likely benign Hereditary spastic paraplegia 3A 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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