ClinVar Miner

Submissions for variant NM_014159.7(SETD2):c.68C>G (p.Pro23Arg)

gnomAD frequency: 0.00001  dbSNP: rs892374525
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001066060 SCV001231054 uncertain significance Luscan-Lumish syndrome 2019-05-29 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. This variant has not been reported in the literature in individuals with SETD2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with arginine at codon 23 of the SETD2 protein (p.Pro23Arg). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and arginine.
Baylor Genetics RCV001066060 SCV001526396 uncertain significance Luscan-Lumish syndrome 2018-03-12 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab RCV001066060 SCV002554272 uncertain significance Luscan-Lumish syndrome 2022-03-15 criteria provided, single submitter clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis RCV005051853 SCV005685522 uncertain significance SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth 2024-11-27 criteria provided, single submitter clinical testing The SETD2 c.68C>G (p.Pro23Arg) variant, to our knowledge, has not been reported in the medical literature. This variant is observed on 15/1,306,062 alleles in the general population (gnomAD v.4.1.0). Computational predictors suggest that the variant does not impact SETD2 structure and function but may affect RNA splicing. No functional studies have been published to confirm these predictions. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.

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