Submissions for variant NM_207581.4(DUOXA2):c.205+2T>C

gnomAD frequency: 0.00029  dbSNP: rs201506037

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255221	SCV000321568	uncertain significance	not provided	2019-07-15	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31980526, 31589614, 33692749)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255221	SCV001076344	benign	not provided	2023-09-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002521850	SCV003753528	likely benign	Inborn genetic diseases	2021-07-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
3billion, Medical Genetics	RCV000991175	SCV003841734	pathogenic	Thyroglobulin synthesis defect	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: 0.046%). This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported to be associated with DUOXA2 related disorder (ClinVar ID: VCV000265105). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005238806	SCV003934275	uncertain significance	not specified	2024-12-17	criteria provided, single submitter	clinical testing	Variant summary: DUOXA2 c.205+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of DUOXA2 function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. One predict the variant weakens the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00048 in 250150 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DUOXA2 causing Thyroglobulin synthesis defect, allowing no conclusion about variant significance. c.205+2T>C has been reported in the literature as a non-informative genotype (a second variant presumably in cis or a heterozygous genotype) in settings of multigene panel analysis in cohorts of individuals with Congenital Hypothyroidism due to Dyshormonogenesis or deeply phenotyped adults undergoing whole genome sequencing (example, Stoupa_2020, Hou_2020). It has also been observed as a non-informative genotype in settings of multiomic analyses in human participants of a wellness program (example, Grasberger_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Thyroglobulin synthesis defect. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33651715, 31980526, 33692749). ClinVar contains an entry for this variant (Variation ID: 265105). Based on the evidence outlined above, the variant was classified as uncertain significance.
Reproductive Health Research and Development, BGI Genomics	RCV000991175	SCV001142449	uncertain significance	Thyroglobulin synthesis defect	2020-01-06	no assertion criteria provided	curation	NG_016992.1(NM_207581.3):c.205+2T>C in the DUOXA2 gene has an allele frequency of 0.01 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant destroys the canonical splice donor site. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product if the message is used for protein translation. The c.205+2T>C variant has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PVS1.
Polak associated Lab, IMAGINE Institute	RCV001270332	SCV001450555	pathogenic	Congenital hypothyroidism		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004758679	SCV005352283	likely pathogenic	DUOXA2-related disorder	2024-07-22	no assertion criteria provided	clinical testing	The DUOXA2 c.205+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported, along with another missense variant in DUOXA2 and two additional variants in the TG gene, in an individual with congenital thyroid dyshormonogenesis (Patient 8, Stoupa et al. 2020. PubMed ID: 33692749). Of note, family follow-up testing to determine phase of the DUOXA2 or TG variants in that patient were not performed. Gene disrupting variants in DUOXA2 are expected to be pathogenic and are associated with autosomal recessive thyroid dyshormonogenesis 5 (OMIM: #612772; Human Gene Mutation Database). In summary, we interpret this variant as likely pathogenic.