ClinVar Miner

Submissions for variant NM_018965.4(TREM2):c.407G>A (p.Arg136Gln)

gnomAD frequency: 0.00007  dbSNP: rs149622783
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000593199 SCV000703534 uncertain significance not provided 2018-07-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000593199 SCV002206039 uncertain significance not provided 2023-12-15 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 136 of the TREM2 protein (p.Arg136Gln). This variant is present in population databases (rs149622783, gnomAD 0.03%). This missense change has been observed in individual(s) with Alzheimer disease (PMID: 23150934, 24899047, 36112222, 36133075). ClinVar contains an entry for this variant (Variation ID: 498494). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects TREM2 function (PMID: 27589997). 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.
CeGaT Center for Human Genetics Tuebingen RCV000593199 SCV004161593 likely benign not provided 2024-05-01 criteria provided, single submitter clinical testing TREM2: BP4
PreventionGenetics, part of Exact Sciences RCV004751612 SCV005353082 uncertain significance TREM2-related disorder 2024-09-08 no assertion criteria provided clinical testing The TREM2 c.407G>A variant is predicted to result in the amino acid substitution p.Arg136Gln. This variant has been associated with increased risk for Alzheimer disease (Jin et al. 2014. PubMed ID: 24899047; Guerreiro et al. 2012. PubMed ID: 23150934). Measured soluble TREM2 protein levels using cerebrospinal fluid from individuals carrying this variant were demonstrated to be lower compared to controls (Piccio et al. 2016. PubMed ID: 26754641). Additional in vitro functional studies using HEK293 cells demonstrated a modest reduction in cell surface expression (Sirkis et al. 2016. PubMed ID: 27589997). This variant is reported in 0.025% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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