Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001812275 | SCV001470794 | likely pathogenic | not provided | 2019-10-03 | criteria provided, single submitter | clinical testing | The MEN1 c.124G>A; p.Gly42Ser variant is reported in the literature in several individuals affected with MEN1-related hyperparathyroidism and has also been observed as a somatic variant in parathyroid tumor tissue (Kong 2016, Sato 2000). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 42 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (p.Gly42Asp, p.Gly42Val) have been reported in individuals with MEN1 and are considered disease-causing (Bassett 1998, Itoh 2017). Based on available information, the p.Gly42Ser variant is considered to be likely pathogenic. References: Bassett JH et al. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet. 1998 Feb;62(2):232-44. Itoh M and Saikawa Y. A novel MEN1 mutation in a Japanese adolescent with multiple endocrine neoplasia type 1. Clin Pediatr Endocrinol. 2017 Jan;26(1):25-28. Kong J et al. Clinical and Genetic Analysis of Multiple Endocrine Neoplasia Type 1-Related Primary Hyperparathyroidism in Chinese. PLoS One. 2016 Nov 15;11(11):e0166634. Sato K et al. Somatic mutations of the multiple endocrine neoplasia type 1 (MEN1) gene in patients with sporadic, nonfamilial primary hyperparathyroidism. Surgery. 2000 Mar;127(3):337-41. |
| Invitae | RCV001302220 | SCV001491418 | uncertain significance | Multiple endocrine neoplasia, type 1 | 2020-07-26 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine with serine at codon 42 of the MEN1 protein (p.Gly42Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of multiple endocrine neoplasia type 1 (PMID: 27846313). 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. This variant disrupts the p.Gly42 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been observed in individuals with MEN1-related conditions (PMID: 28203045, 29066490, 9463336), which suggests that this may be a clinically significant amino acid residue. 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. |