rs530719719

chr15-45101227-TGAAC-Tchr15-45101227-TGAAC-TGAACGAAC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_001363711.2(DUOX2):c.2895_2898del(p.Phe966SerfsTer29) variant causes a frameshift change. The variant allele was found at a frequency of 0.00284 in 1,613,794 control chromosomes in the GnomAD database, including 14 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S965S) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (12 hom.)
• Consequence: DUOX2 NM_001363711.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 4.91

Genes affected

DUOX2 (HGNC:13273): (dual oxidase 2) The protein encoded by this gene is a glycoprotein and a member of the NADPH oxidase family. The synthesis of thyroid hormone is catalyzed by a protein complex located at the apical membrane of thyroid follicular cells. This complex contains an iodide transporter, thyroperoxidase, and a peroxide generating system that includes this encoded protein and DUOX1. This protein is known as dual oxidase because it has both a peroxidase homology domain and a gp91phox domain. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-45101227-TGAAC-T is Pathogenic according to our data. Variant chr15-45101227-TGAAC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45101227-TGAAC-T is described in Lovd as [Pathogenic].
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUOX2	NM_001363711.2	c.2895_2898del	p.Phe966SerfsTer29	frameshift_variant	22/34	ENST00000389039.11
DUOX2	NM_014080.5	c.2895_2898del	p.Phe966SerfsTer29	frameshift_variant	22/34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUOX2	ENST00000389039.11	c.2895_2898del	p.Phe966SerfsTer29	frameshift_variant	22/34	1	NM_001363711.2	P4
DUOX2	ENST00000603300.1	c.2895_2898del	p.Phe966SerfsTer29	frameshift_variant	22/34	1		A1
DUOX2	ENST00000558383.1	n.5144_5147del		non_coding_transcript_exon_variant	15/17	5
DUOX2	ENST00000558416.1	n.109_112del		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 397 AN: 152176 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00979

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00315

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00294 AC: 736 AN: 250634 Hom.: 5 AF XY: 0.00288 AC XY: 391 AN XY: 135530

Gnomad AFR exome AF: 0.000621

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00213

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.00291

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00286 AC: 4183 AN: 1461500 Hom.: 12 AF XY: 0.00287 AC XY: 2087 AN XY: 726996

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00265

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.00279

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00261 AC: 398 AN: 152294 Hom.: 2 Cov.: 32 AF XY: 0.00279 AC XY: 208 AN XY: 74470

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00979

Gnomad4 NFE AF: 0.00315

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000667 Hom.: 0

Bravo AF: 0.00207

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00360

EpiControl AF: 0.00273

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thyroid dyshormonogenesis 6 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Sep 24, 2019	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 11, 2022	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 02, 2017	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2021

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. -

DUOX2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2024

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. -

Congenital hypothyroidism Pathogenic:1

Pathogenic, no assertion criteria provided

curation

Reproductive Health Research and Development, BGI Genomics

Jan 06, 2020

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 -

Nongoitrous Euthyroid Hyperthyrotropinemia Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Jan 01, 2017

- -

Familial thyroid dyshormonogenesis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 16, 2020

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 PMID:16322276, Chiesa 2010 PMID:20972728, De Marco 2011 PMID:21565790, Moreno 2012 PMID:12110737, Muzza 2014 PMID:24423310, Kizys 2017 PMID:28666341, Srichomkwun 2017 PMID:27821020, Makretskaya 2018 PMID:30240412). 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 hydrogen peroxide-generating activity as well as decreased cell surface expression compared to wild-type (De Marco 2011 PMID:21565790). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: -22

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs530719719; hg19: chr15-45393425;