11-64808079-C-G
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001370259.2(MEN1):c.466G>C(p.Gly156Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G156C) has been classified as Pathogenic.
Frequency
Consequence
NM_001370259.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MEN1 | NM_001370259.2 | c.466G>C | p.Gly156Arg | missense_variant | Exon 3 of 10 | ENST00000450708.7 | NP_001357188.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 1 Pathogenic:1
Variant summary: MEN1 c.466G>C (p.Gly156Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Other variants located at the same codon have been reported in association with Multiple Endocrine Neoplasia Type 1 in the HGMD database, supporting a critical role of this location in Menin, the MEN1 encoded protein. The variant was absent in 246660 control chromosomes. c.466G>C has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 1 (example, PMID: 17766710, 28458907). Recently the French oncogenetics network of neuroendocrine tumors (TENGEN) has proposed this variant be classified as pathogenic using adjustments to the ACMG-AMP framework for the interpretation of MEN1 missense variants (PMID: 30869828). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:1
The G156R variant in the MEN1 gene has previously been reported in multiple individuals with multiple endocrine neoplasia type 1 (Vierimaa et al., 2007; Uraki et al., 2017). This variant is not observed in large population cohorts (Lek et al., 2016). The G156R 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (G156S, G156C, G156V, G156D), as well as nearby residues (D153Y, D153V, D153E, S154I, S155F, A158D, A160P, A160T) have been reported in the Human Gene Mutation Database in association with MEN1-related disorders (Mutch et al., 1999; Tham et al., 2007; Belar et al., 2012; Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at