Submissions for variant NM_001363711.2(DUOX2):c.2048G>T (p.Arg683Leu)

dbSNP: rs8028305

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000929394	SCV001075024	likely benign	not provided	2024-10-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001121493	SCV001280114	uncertain significance	Thyroid dyshormonogenesis 6	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000929394	SCV001987720	likely pathogenic	not provided	2023-06-22	criteria provided, single submitter	clinical testing	Reported in the homozygous and heterozygous states in individuals with congenital hypothyroidism (CH) or thyroid dyshormonogenesis (DH), however many affected individuals harbored one or more additional variants in DUOX2 and/or other CH- or DH-associated genes, making it difficult to determine the pathogenicity of this variant (Fu et al., 2015; Fu et al., 2016; Fan et al., 2017; Chen et al., 2018; Jiang et al., 2016; Peters et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 34539567, 29779043, 27256230, 27173810, 29146476, 31356790, 26349762, 27108200, 28215547, 30022773, 30154845, 27498126, 31044655, 32425884, 33631011, 33490161, 33628596, 33310921, 36207832, 37147621, 34767783, 36555929)
3billion	RCV001121493	SCV005904668	uncertain significance	Thyroid dyshormonogenesis 6	2023-08-07	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: 0.034%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.43 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.83 (>=0.6, sensitivity 0.72 and precision 0.9)). A different missense change at the same codon (p.Arg683Cys) has been reported to be associated with DUOX2 related disorder (PMID: 33651715). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.