ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.1267G>C (p.Asp423His) (rs104894264)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182455 SCV000234800 pathogenic not provided 2015-09-08 criteria provided, single submitter clinical testing The D418H missense mutation in the MEN1 gene has been reported previously in association with familial isolated hyperparathyroidism (Warner et al., 2004) and multiple endocrine neoplasia type 1 (MEN1) (Jap et al., 2005). Another missense mutation at this codon, D418N, also has been reported in association with MEN1 (Bassett et al., 1998). The variant is found in MEN1 panel(s).
Invitae RCV001044491 SCV001208292 likely pathogenic Multiple endocrine neoplasia, type 1 2019-03-25 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 418 of the MEN1 protein (p.Asp418His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with multiple endocrine neoplasia type 1 (MEN1) in a family (PMID: 15730416) and has been observed in several individuals affected with clinical features of MEN1 (PMID: 14985373, 16430712, 25309785). ClinVar contains an entry for this variant (Variation ID: 201015). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Asp418 amino acid residue in MEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9463336, 11303512, 11836268, 17766710, 12050235). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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