ClinVar Miner

Submissions for variant NM_001370259.2(MEN1):c.511C>T (p.Arg171Trp) (rs143329068)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410523 SCV000488525 uncertain significance Multiple endocrine neoplasia, type 1 2016-04-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000455664 SCV000539620 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband, multiple reports classify as non-pathogenic; ClinVar: 1 LB
Invitae RCV000410523 SCV000541235 uncertain significance Multiple endocrine neoplasia, type 1 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 171 of the MEN1 protein (p.Arg171Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs143329068, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with hyperparathyroidism (PMID: 16563611). ClinVar contains an entry for this variant (Variation ID: 161294). Experimental studies have shown that this missense change does not appreciably affect protein stability (PMID: 21819486). 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.
GeneDx RCV000766972 SCV000568652 uncertain significance not provided 2017-01-12 criteria provided, single submitter clinical testing This variant is denoted MEN1 c.511C>T at the cDNA level, p.Arg171Trp (R171W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). Using alternate nomenclature, this variant has also been reported as c.526C>G (p.Arg176Trp). This variant was observed in a Danish individual with primary hyperparathyroidism (Jäger 2006). In vitro studies show that MEN1 Arg171Trp does not significantly reduce menin expression compared to normal controls (Shimazu 2011). MEN1 Arg171Trp was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MEN1 Arg171Trp occurs at a position that is conserved in mammals and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MEN1 Arg171Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569499 SCV000673624 likely benign Hereditary cancer-predisposing syndrome 2018-05-25 criteria provided, single submitter clinical testing Other strong data supporting benign classification;Intact protein function observed in appropriate functional assay(s)
Mendelics RCV000410523 SCV001138344 benign Multiple endocrine neoplasia, type 1 2019-05-28 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148612 SCV000190327 likely benign Hyperparathyroidism 2014-06-01 no assertion criteria provided research

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