ClinVar Miner

Submissions for variant NM_001135659.2(NRXN1):c.3223A>G (p.Thr1075Ala) (rs753262049)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726048 SCV000341502 uncertain significance not provided 2016-06-02 criteria provided, single submitter clinical testing
GeneDx RCV000726048 SCV000618944 uncertain significance not provided 2017-07-11 criteria provided, single submitter clinical testing The T1075A variant has not been published as a pathogenic variant, nor has it been reported as abenign variant to our knowledge. It is not observed at a significant frequency in large populationcohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Thisvariant is a non-conservative amino acid substitution that occurs at a position that is not conserved.In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to theprotein structure/function. Therefore, based on the currently available information, it is unclearwhether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000817074 SCV000957614 uncertain significance Pitt-Hopkins-like syndrome 2 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1075 of the NRXN1 protein (p.Thr1075Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs753262049, ExAC 0.002%). This variant has not been reported in the literature in individuals with NRXN1-related disease. ClinVar contains an entry for this variant (Variation ID: 287664). 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.

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