ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.683T>C (p.Leu228Pro) (rs886039415)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255095 SCV000321880 pathogenic not provided 2019-07-02 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12112656, 9683585, 22470073, 12652570, 30869828, 28597079, 11836268, 10849016)
Ambry Genetics RCV000491535 SCV000579636 likely pathogenic Hereditary cancer-predisposing syndrome 2017-11-08 criteria provided, single submitter clinical testing The p.L223P variant (also known as c.668T>C) is located in coding exon 3 of the MEN1 gene. This alteration results from a T to C substitution at nucleotide position 668. The leucine at codon 223 is replaced by proline, an amino acid with a few similar properties. This alteration has been reported multiple unrelated individuals meeting clinical diagnostic criteria for multiple endocrine neoplasia type 1 (MEN1) (Giraud S et al. Am J Hum Genet. 1998 Aug;63(2):455-67; Roijers J et al. Eur J Clin Invest. 2000 Jun;30(6):487-92; Verges B et al. J Clin Endocrinol Metab. 2002 Feb;87(2):457-65; Wautot V et al. Hum Mut. 2002;20(1):35-47). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV001235431 SCV001408116 likely pathogenic Multiple endocrine neoplasia, type 1 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 223 of the MEN1 protein (p.Leu223Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with multiple endocrine neoplasia type 1 (PMID: 9683585, 12112656, 10849016, Invitae). This variant is also known in the literature as c.683T>C (p.Leu228Pro). ClinVar contains an entry for this variant (Variation ID: 265236). 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). 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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