Submissions for variant NM_001363711.2(DUOX2):c.2895_2898del (p.Phe966fs)

dbSNP: rs530719719

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169659	SCV000221187	pathogenic	Familial thyroid dyshormonogenesis	2019-03-15	criteria provided, single submitter	clinical testing	The p.Phe966SerfsX29 variant in DUOX2 has been reported in at least 30 individuals with congenital hypothyroidism, of whom 7 were homozygous, 4 were reportedly compound heterozygous (although only 2 individuals were compound heterozygous for a clearly pathogenic variant), and 19 were heterozygous (Varela 2006, Chiesa 2010, De Marco 2011, Moreno 2012, Muzza 2014, Kizys 2017, Srichomkwun 2017, Makretskaya 2018). It has also been identified in 0.29% (829/281197) of total chromosomes, including 1.16% of Finnish chromosomes and 6 homozygous individuals, by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Functional studies demonstrate that this variant results in complete inhibition of the hydrogen peroxide-generating activity as well as decreased cell surface expression compared to wild-type (De Marco 2011). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 966 and leads to a premature termination codon 29 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the DUOX2 gene is an established disease mechanism in autosomal recessive congenital hypothyroidism. Finally, this variant has been reported as pathogenic and likely pathogenic in ClinVar (Variation ID 189229). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital hypothyroidism. ACMG/AMP Criteria applied: PVS1, PM3, PS3_Supporting.
GeneDx	RCV000256134	SCV000321567	pathogenic	not provided	2022-08-02	criteria provided, single submitter	clinical testing	Reported in the published literature, as S965fsX994 due to alternate nomenclature, in the heterozygous or compound heterozygous state in multiple individuals with partial iodide-organification defects and transient or permanent congenital hypothyroidism (Moreno et al., 2002; De Marco et al., 2011; Muzza et al., 2014); Published functional studies demonstrate complete inhibition of the hydrogen peroxide-generating activity as well as decreased cell surface expression (De Marco et al., 2011); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27821020, 30487145, 30609409, 31030636, 16322276, 24423310, 12110737, 28666341, 26990548, 30084132, 30240412, 31044655, 31028847, 32109542, 33124651, 31980526, 31589614, 33144682, 32765423, 34426522, 34248839, 21565790)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000256134	SCV000511719	pathogenic	not provided	2017-02-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624099	SCV000742851	pathogenic	Inborn genetic diseases	2021-03-24	criteria provided, single submitter	clinical testing	The c.2895_2898delGTTC (p.F966Sfs*29) alteration, located in exon 22 (coding exon 21) of the DUOX2 gene, results from a deletion of 4 nucleotides from position 2895 to 2898, causing a translational frameshift with a predicted alternate stop codon after 29 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD), the DUOX2 c.2895_2898delGTTC alteration was observed in 0.29% (829/282026) of total alleles studied, with a frequency of 1.16% (292/25102) in the European (Finnish) subpopulation. This mutation has been observed in the homozygous, heterozygous, and compound heterozygous states in multiple unrelated individuals with both transient and permanent congenital hypothyroidism (CH) (Moreno, 2002; De Marco, 2011; Muzza, 2014; Abulí, 2016; Srichomkwun, 2017; Kizys, 2017; Repnikova, 2018; Makretskaya, 2018; Peters, 2019). This amino acid position is highly conserved in available vertebrate species. Functional in vitro analyses performed on this mutation demonstrate nearly complete inhibition of hydrogen peroxide generation (De Marco, 2011; Muzza, 2014) and reduced cell surface protein expression compared to wildtype (De Marco, 2011). Based on the available evidence, this alteration is classified as pathogenic.
Invitae	RCV000256134	SCV000951183	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe966Serfs*29) in the DUOX2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DUOX2 are known to be pathogenic (PMID: 12110737, 18765513, 21565790, 24423310, 24735383). This variant is present in population databases (rs530719719, gnomAD 1.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with partial iodide organification defect (PMID: 21565790, 24423310). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189229). For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001265562	SCV001443718	likely pathogenic	Thyroid dyshormonogenesis 6	2019-09-24	criteria provided, single submitter	clinical testing	A heterozygous c.2895_2898del (p.Phe966SerfsTer29) variant in DUOX2, also referred to as S965fsX994 in the literature, was detected in this individual. This four bp deletion in exon 22 of DUOX2, sometimes referred to as S965fsX994 in the literature, causes a frameshift and a premature stop codon at residue 994, and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. In the gnomAD population database this variant is present as heterozygous at a frequency of 0.297% (820/276458) and as homozygous in six individuals. This variant is a recurrent pathogenic alteration that has been reported in the literature as homozygous or compound heterozygous in multiple individuals with partial iodide-organification defects and transient or permanent congenital hypothyroidism (PMID: 12110737, 21565790, 24423310, 28666341, 31044655). This variant was shown to results in nonsense mediated mRNA decay (PMID: 24423310) and complete inhibition of the hydrogen peroxide-generating activity as well as decreased cell surface expression in in-vitro experiments based on expression of wild-type and mutant cDNA constructs in Hela cells (PMID: 24423310, 21565790). ClinVar contains an entry for this variant (Variation ID: 189229). Based on the available evidence, the c.2895_2898del (p.Phe966SerfsTer29) variant is classified as Likely Pathogenic.
Mendelics	RCV001265562	SCV002519586	pathogenic	Thyroid dyshormonogenesis 6	2022-05-04	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV001265562	SCV002761908	pathogenic	Thyroid dyshormonogenesis 6	2022-07-11	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001265562	SCV003831676	likely pathogenic	Thyroid dyshormonogenesis 6	2022-04-02	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV001265562	SCV004047016	pathogenic	Thyroid dyshormonogenesis 6		criteria provided, single submitter	clinical testing	The frameshift c.2895_2898del (p.Phe966SerfsTer29) variant has been reported previously in homozygous and compound heterozygous state in patients affected with dyshormonogenic congenital hypothyroidism. Experimental studies have shown that this frameshift variant results in nonsense mediated decay (Muzza M. et al. 2014). The variant is reported with the allele frequency of 0.3% in gnomAD Exomes and 0.2% in 1000 Genomes. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003398870	SCV004119233	pathogenic	DUOX2-related condition	2024-01-04	criteria provided, single submitter	clinical testing	The DUOX2 c.2895_2898delGTTC variant is predicted to result in a frameshift and premature protein termination (p.Phe966Serfs*29). This variant has been reported in homozygous and compound heterozygous individuals diagnosed with congenital hypothyroidism (Muzza et al. 2013. PubMed ID: 24423310; Makretskaya et al. 2018. PubMed ID: 30240412). This variant in the heterozygous state may be associated with some mild clinical features of the disease (Patient 4 in Moreno et al. 2002. PubMed ID: 12110737; F23 in Nicholas et al. 2016. PubMed ID: 27525530). In the ClinVar database, this variant has been listed as likely pathogenic or pathogenic by multiple submitters (https://preview.ncbi.nlm.nih.gov/clinvar/variation/189229/). This variant is reported in 1.2% of alleles in individuals of European (Finnish) descent in gnomAD, including 6 homozygotes. Frameshift variants in DUOX2 are expected to be pathogenic. This variant is interpreted as pathogenic.
University of Washington Center for Mendelian Genomics, University of Washington	RCV000755102	SCV000882920	likely pathogenic	Nongoitrous Euthyroid Hyperthyrotropinemia	2017-01-01	no assertion criteria provided	research
Reproductive Health Research and Development, BGI Genomics	RCV000991174	SCV001142447	pathogenic	Congenital hypothyroidism	2020-01-06	no assertion criteria provided	curation	NM_014080.4:c.2895_2898delGTTC in the DUOX2 gene has an allele frequency of 0.012 in European (Finnish) subpopulation in the gnomAD database.This variant is located in the 22nd exon (a total of 34 exons in the NM_014080.4 transcript), therefore, it is predicted to result in nonsense-mediated mRNA decay. Muzza et al reported four independent Italian families with dyshormonogenic Congenital Hypothyroidism, revealing compound heterozygous in trans (PMID: 24423310). Functional studies confirmed that this mutation is responsible for the defect in H2O2 production (PMID: 21565790). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PS3; PM3_Strong