Submissions for variant NM_001370259.2(MEN1):c.537G>C (p.Glu179Asp)

dbSNP: rs1555165811

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521106	SCV000620425	uncertain significance	not provided	2017-08-24	criteria provided, single submitter	clinical testing	The E179D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E179D variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. An alternate nucleotide change leading to the same missense variant (c.537G>T) has been reported in association with multiple endocrine neoplasia type 1, supporting the functional importance of this region of the protein (Poncin et al., 1999). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001228587	SCV001400992	pathogenic	Multiple endocrine neoplasia, type 1	2022-04-06	criteria provided, single submitter	clinical testing	This variant disrupts the p.179 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been observed in individuals with MEN1-related conditions (PMID: 9888389, 10849016, 11102994, 22470073), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MEN1 protein function. ClinVar contains an entry for this variant (Variation ID: 451692). This variant is also known as p.Glu184Asp. This missense change has been observed in individuals with clinical features of MEN1 (PMID: 9888389; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 179 of the MEN1 protein (p.Glu179Asp). For these reasons, this variant has been classified as Pathogenic.