Submissions for variant NM_001370259.2(MEN1):c.1174del (p.Glu392fs)

dbSNP: rs386134247

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255795	SCV000321884	likely pathogenic	not provided	2017-03-30	criteria provided, single submitter	clinical testing	The c.1174delG variant has been reported previously (as 1280delG) in association with multiple endocrine neoplasia type 1 (Agarwal et al., 1997). The c.1174delG variant causes a frameshift starting with codon Glutamic acid 392, changes this amino acid to a Serine residue and creates a premature Stop codon at position 53 of the new reading frame, denoted p.Glu392SerfsX53. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1174delG 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. Based on currently available evidence, c.1174delG is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded.
Department of Laboratory Medicine, Soonchunhyang University Seoul Hospital	RCV000714231	SCV000834125	pathogenic	Multiple endocrine neoplasia, type 1	2018-01-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000714231	SCV001400770	pathogenic	Multiple endocrine neoplasia, type 1	2019-10-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with multiple endocrine neoplasia type 1 (PMID: 9215689). This variant is also known as 1280delG in the literature. ClinVar contains an entry for this variant (Variation ID: 265238). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the MEN1 gene (p.Glu392Serfs*53). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 219 amino acids of the MEN1 protein. This variant disrupts the C-terminus of the MEN1 protein. Other variant(s) that disrupt this region (p.Lys559Glufs*38) have been determined to be pathogenic (PMID: 10090472, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease.
Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)	RCV000714231	SCV003930414	pathogenic	Multiple endocrine neoplasia, type 1	2023-05-10	criteria provided, single submitter	clinical testing