Submissions for variant NM_001182.5(ALDH7A1):c.203C>A (p.Thr68Asn) (rs58528748)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital	RCV000678776	SCV000804955	uncertain significance	Intractable seizure	2017-02-10	no assertion criteria provided	clinical testing
GeneDx	RCV000186731	SCV000240298	uncertain significance	not provided	2018-12-17	criteria provided, single submitter	clinical testing	Functional studies of the T68N variant suggests that the variant may impact enzyme function (Coughlin et al., 2018). This variant is observed in 29/24000 (0.1%) alleles from individuals of African background (Lek et al., 2016). The T68N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter 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	RCV000641168	SCV000762805	uncertain significance	Pyridoxine-dependent epilepsy	2018-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with asparagine at codon 68 of the ALDH7A1 protein (p.Thr68Asn). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and asparagine. This variant is present in population databases (rs58528748, ExAC 0.2%). This variant has not been reported in the literature in individuals with ALDH7A1-related disease. ClinVar contains an entry for this variant (Variation ID: 204835). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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