Submissions for variant NM_001330078.2(NRXN1):c.570C>A (p.Asn190Lys) (rs564945882)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188274	SCV000241884	uncertain significance	not provided	2012-09-26	criteria provided, single submitter	clinical testing	The Asn190Lys missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Asn190Lys in approximately 6,200 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as an uncharged Asparagine residue is replaced by a positively charged Lysine residue. Asn190Lys alters a position that is not conserved in the neurexin1 protein but is highly conserved in related proteins, and several in silico algorithms predict Asn190Lys may be damaging to protein structure/function. Therefore, based on the currently available information, it is unclear whether Asn190Lys is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae	RCV000818582	SCV000959202	uncertain significance	Pitt-Hopkins-like syndrome 2	2018-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with lysine at codon 190 of the NRXN1 protein (p.Asn190Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs564945882, ExAC 0.03%). This variant has not been reported in the literature in individuals with NRXN1-related disease. ClinVar contains an entry for this variant (Variation ID: 206244). 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"). 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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