ClinVar Miner

Submissions for variant NM_001363711.2(DUOX2):c.1946C>A (p.Ala649Glu)

dbSNP: rs748793969
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000778437 SCV000914683 likely pathogenic Thyroid dyshormonogenesis 6 2017-12-28 criteria provided, single submitter clinical testing The DUOX2 c.1946C>A (p.Ala649Glu) variant has been reported in at least three studies and is found in a total of six individuals including five in a compound heterozygous state (including two siblings), and one in a heterozygous state (Maruo et al. 2008; Park et al. 2016; Srichomkwun et al. 2017). The p.Ala649Glu variant was absent from 100 control chromosome and is reported at a frequency of 0.00046 in the South Asian population of the Genome Aggregation Database. Based on the evidence, the p.Ala649Glu variant is classified as likely pathogenic for congenital hypothyroidism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV002533117 SCV003287105 uncertain significance not provided 2022-06-30 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 649 of the DUOX2 protein (p.Ala649Glu). This variant is present in population databases (rs748793969, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of DUOX2-related conditions (PMID: 18765513, 26709262, 27821020, 29650690, 32459320). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 617814). 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 disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
3billion RCV000778437 SCV003841620 likely pathogenic Thyroid dyshormonogenesis 6 2023-02-23 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Protein truncation variants are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with DUOX2-related disorder (ClinVar ID: VCV000617814 / PMID: 18765513). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 18765513, 26709262, 27821020). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
University of Washington Center for Mendelian Genomics, University of Washington RCV000755099 SCV000882917 likely pathogenic Nongoitrous Euthyroid Hyperthyrotropinemia 2017-01-01 no assertion criteria provided research

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