chr15-45101227-TGAAC-T

Position:

chr15-45101227-TGAAC-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

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

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 4.91

Variant links:

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]

DUOX2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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].

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.00261

AC:

397

AN:

152176

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00288

AC XY:

391

AN XY:

135530

show subpopulations

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.:

AF XY:

0.00287

AC XY:

2087

AN XY:

726996

show subpopulations

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.:

Cov.:

AF XY:

0.00279

AC XY:

208

AN XY:

74470

show subpopulations

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.:

Bravo

AF:

0.00207

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00360

EpiControl

AF:

0.00273

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Thyroid dyshormonogenesis 6

Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 21, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 02, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 11, 2022	- -
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, no assertion criteria provided	clinical testing	Breakthrough Genomics, Breakthrough Genomics	-	This variant has been previously reported in patients with congenital hypothyroidism in homozygous or compound heterozygous state and classified as pathogenic [PMID: 30240412, 28666341, 27821020, 24423310]. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 02, 2017	- -
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	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) -

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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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