Submissions for variant NM_170707.4(LMNA):c.242A>G (p.Tyr81Cys)

dbSNP: rs879254319

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000237077	SCV000294174	uncertain significance	not provided	2016-04-26	criteria provided, single submitter	clinical testing	The Y81C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y81C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, the Y81C 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. Additionally, this substitution occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to damaging to the protein structure/function.
Invitae	RCV001351546	SCV001546026	uncertain significance	Charcot-Marie-Tooth disease type 2	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 81 of the LMNA protein (p.Tyr81Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 246580). 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 disruptive. 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.