Submissions for variant NM_001363711.2(DUOX2):c.2654G>T (p.Arg885Leu)

dbSNP: rs181461079

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778436	SCV000914681	likely pathogenic	Thyroid dyshormonogenesis 6	2018-10-31	criteria provided, single submitter	clinical testing	The c.2654G>T (p.Arg885Leu) variant is a missense variant that is predicted to affect the nucleotide immediately upstream of a donor splice site. The p.Arg885Leu variant has been reported in at least seven individuals with congenital hypothyroidism, including in trans with a missense variant in a Japanese individual diagnosed with dyshormonogenesis (Narumi et al. 2011), in a heterozygous state with two other missense variants (zygosity unspecified) in a 15-month-old Chinese male (Jiang et al. 2016), in a heterozygous state with a second DUOX2 variant (zygosity unspecified) in a five-month-old male Chinese individual who also carried a splice variant in SLC26A4 (Jiang et al. 2016), and in trans with a complex allele containing two missense variants in two Japanese siblings who showed elevated serum TSH with normal thyroid hormone concentrations and small, eutrophic thyroid glands on ultrasound (Srichomkwun et al. 2017). The father of these individuals, who was heterozygous for the p.Arg885Leu variant, was hypothyroid. Notably, there is a discrepancy in the nomenclature used to refer to the variant in the pedigree presented by Srichomkwun et al. (2017). In addition, two sisters with goitrous congenital hypothyroidism were found to be heterozygous for the p.Arg885Leu variant and a missense variant in the DUOXA2 gene (Zheng et al. 2017); within this family, two heterozyous carriers of p.Arg885Leu showed normal thyroid function. The p.Arg885Leu variant was absent from 105 control individuals and is reported at a frequency of 0.005777 in the East Asian population of the Genome Aggregation Database. Functional studies of the variant have not been conducted. Narumi et al. (2011) report that RT-PCR and sequencing of lymphoblastic RNA from the compound heterozygous patient showed that mRNA harboring the p.Arg885Leu variant was not expressed, likely due to erroneous splicing; however, these data are not shown. Based on the collective evidence, the p.Arg885Leu 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	RCV000890156	SCV001033887	uncertain significance	not provided	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 885 of the DUOX2 protein (p.Arg885Leu). This variant is present in population databases (rs181461079, gnomAD 0.6%). This missense change has been observed in individual(s) with congenital hypothyroidism and thyroid dyshormonogenesis (PMID: 21900383, 27498126, 28541007, 29650690, 30512158, 32319661, 32425884, 34276565). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 617815). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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.
Genetic Services Laboratory, University of Chicago	RCV000890156	SCV002067538	likely pathogenic	not provided	2020-09-01	criteria provided, single submitter	clinical testing	DNA sequence analysis of the DUOX2 gene demonstrated two sequence changes. The first sequence change, c.2654G>T in exon 20, results in an amino acid change, p.Arg885Leu. This sequence change has been described in the gnomAD database with a population frequency of 0.041% (dbSNP rs181461079). The p.Arg885Leu change affects a highly conserved amino acid residue located in a domain of the DUOX2 protein that is known to be functional. The p.Arg885Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD). This particular amino acid change has been reported in the compound heterozygous state with a second DUOX2 pathogenic variant in multiple individuals with congenital hypothyroidism (PMIDs: 27498126, 30512158, 30894704, 28541007). The c.2654G>T (p.Arg885Leu) sequence change has also been reported in the compound heterozygous state with the c.3329G>A (p.Arg1110Gln) sequence change in one individual with congenital hypothyroidism (PMID: 27498126). Furthermore, a different amino acid change at this same position (p.Arg885Gln) has been reported in multiple individuals with congenital hypothyroidism (PMIDs: 30154845, 30022773, 25248169). Collectively, these evidences indicate that c. 2654G>T (p.Arg885Leu) sequence change is likely pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000778436	SCV004175678	likely pathogenic	Thyroid dyshormonogenesis 6	2022-09-19	criteria provided, single submitter	clinical testing	The DUOX2 c.2654G>T variant is classified as Likely Pathogenic (PP3, PM3_Strong, PM5) The DUOX2 c.2654G>T variant is located in the last nucleotide of exon 20/34 of the DUOX2 gene. The variant is predicted to change the amino acid arginine at position 885 in the protein to leucine. Splice-site predictors propose that the c.2654G>T variant results in the loss of a donor splice site (PP3). This variant has been detected in trans with a pathogenic variant in patients with congenital hypothyroidism (PMID:27498126, 32319661, 32319661) (PM3_strong). This variant is a missense change at an amino acid residue where a different missense change has been seen before (c.2654G>A; p.R885Q) (PM5). The variant has been reported in dbSNP (rs181461079) and in the HGMD database (CM1611549). It has been reported as 'Conflicting interpretations of pathogenicity' by other diagnostic laboratories (ClinVar Variation ID: 617815). The variant has been reported in many patients with congenital hypothyroidism (PMID:28541007, 27498126, 29650690, 32425884, 32319661).
Revvity Omics, Revvity	RCV000778436	SCV004238162	likely pathogenic	Thyroid dyshormonogenesis 6	2023-06-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003975299	SCV004789475	likely pathogenic	DUOX2-related condition	2024-02-26	criteria provided, single submitter	clinical testing	The DUOX2 c.2654G>T variant is predicted to result in the amino acid substitution p.Arg885Leu. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with congenital hypothyroidism (see for example, Table 1, Jiang et al. 2016. PubMed ID: 27498126; Table 3, Zheng et al. 2020. PubMed ID: 33490161; Table 1, Huang et al. 2021. PubMed ID: 34276565) and congenital diarrhea with enteropathy (Table S1, Ye et al. 2019. PubMed ID: 30894704). This variant is reported in 0.57% of alleles in individuals of East Asian descent in gnomAD. An alternate nucleotide substitution affecting the same amino acid (p.Arg885Glu) has been reported in multiple individuals with thyroid dyshormonogenesis (Table 1, Long et al. 2018. PubMed ID: 30022773; Table 1, Chen et al. 2018. PubMed ID: 30154845). This variant is interpreted as likely pathogenic.
University of Washington Center for Mendelian Genomics, University of Washington	RCV000755100	SCV000882918	likely pathogenic	Nongoitrous Euthyroid Hyperthyrotropinemia	2017-01-01	no assertion criteria provided	research