ClinVar Miner

Submissions for variant NM_002661.5(PLCG2):c.3755G>C (p.Arg1252Thr)

gnomAD frequency: 0.00002  dbSNP: rs748492148
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000815158 SCV000955604 uncertain significance Familial cold autoinflammatory syndrome 3 2019-02-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 1252 of the PLCG2 protein (p.Arg1252Thr). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and threonine. This variant also falls at the last nucleotide of exon 32 of the PLCG2 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs748492148, ExAC 0.009%). This variant has not been reported in the literature in individuals with PLCG2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Baylor Genetics RCV001330952 SCV001522824 uncertain significance Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation 2019-12-20 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics RCV002507423 SCV002816465 uncertain significance Familial cold autoinflammatory syndrome 3; Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation 2022-04-24 criteria provided, single submitter clinical testing

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