15-45108159-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_001363711.2(DUOX2):c.1462G>A(p.Gly488Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000095 ( 0 hom. )

Consequence

DUOX2
NM_001363711.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.39

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PP5

Variant 15-45108159-C-T is Pathogenic according to our data. Variant chr15-45108159-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUOX2	NM_001363711.2 link	c.1462G>A	p.Gly488Arg	missense_variant	Exon 13 of 34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5 link	c.1462G>A	p.Gly488Arg	missense_variant	Exon 13 of 34		NP_054799.4	Q9NRD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DUOX2	ENST00000389039.11 link	c.1462G>A	p.Gly488Arg	missense_variant	Exon 13 of 34	1	NM_001363711.2	ENSP00000373691.7	X6RAN8
DUOX2	ENST00000603300.1 link	c.1462G>A	p.Gly488Arg	missense_variant	Exon 13 of 34	1		ENSP00000475084.1	Q9NRD8
DUOX2	ENST00000558383.1 link	n.3193G>A		non_coding_transcript_exon_variant	Exon 7 of 17	5

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000135

AC:

AN:

251434

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00130

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000951

AC:

139

AN:

1461854

Hom.:

Cov.:

AF XY:

0.0000935

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00267

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000250

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000196

Hom.:

Bravo

AF:

0.000276

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000181

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Thyroid dyshormonogenesis 6

Pathogenic:4

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

Feb 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2022

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.71; 3Cnet: 0.51). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000225342). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 21900383, 23457309, 25248169, 26709262). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Aug 15, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of the available literature, the DUOX2 c.1462G>A (p.Gly488Arg) missense variant has been reported in at least 18 unrelated patients with congenital hypothyroidism, including in a homozygous state in two siblings and an unrelated individual, in a compound heterozygous state in at least seven individuals, and in a heterozygous state in nine individuals in whom a second variant in the DUOX2 gene was not identified (Narumi et al. 2011; Yoshizawa-Ogasawara et al. 2013; Jin et al. 2014; Park et al. 2016; Srichomkwun et al. 2017). In several of these cases, the variant was shown to be inherited from an unaffected parent. In addition, one patient with dyshormonogenesis and an enlarged thyroid was heterozygous for the p.Gly488Arg variant and a second missense variant, but phase was not specified (Narumi et al. 2011). The p.Gly488Arg variant was absent from at least 100 alleles and is reported at a frequency of 0.001503 in the East Asian population of the Exome Aggregation Consortium. By assaying hydrogen peroxide production, two independent groups showed the variant protein displays greatly reduced activity compared to the wild type protein in HEK293 and A549 cells (Narumi et al. 2011; Jin et al. 2014). Based on the collective evidence, the p.Gly488Arg variant is classified as pathogenic for congenital hypothyroidism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Inborn genetic diseases

Pathogenic:1

Feb 24, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1462G>A (p.G488R) alteration is located in exon 13 (coding exon 12) of the DUOX2 gene. This alteration results from a G to A substitution at nucleotide position 1462, causing the glycine (G) at amino acid position 488 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD) database, the DUOX2 c.1462G>A alteration was observed in 0.015% (42/282816) of total alleles studied, with a frequency of 0.12% (24/19952) in the East Asian subpopulation. This alteration has been detected in multiple individuals with congenital hypothyroidism, in the homozygous state, the compound heterozygous state, and in the heterozygous state without a second alteration identified (Narumi, 2011; Yoshizawa-Ogasawara, 2013; Jin, 2014; Srichomkwun, 2017; Sun, 2018; Abe, 2018; Peters, 2019). This amino acid position is highly conserved in available vertebrate species. A hydrogen peroxide production assay showed significantly decreased hydrogen peroxide compared to wild type protein in HEK293 and A549 cells (Narumi, 2011; Jin, 2014). The in silico prediction for the p.G488R alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

DUOX2-related disorder

Pathogenic:1

Sep 01, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DUOX2 c.1462G>A variant is predicted to result in the amino acid substitution p.Gly488Arg. This variant was reported in individuals with autosomal recessive congenital hypothyroidism and thyroid dyshormonogenesis, with complete loss of function observed in functional in vitro assays (Narumi et al. 2011. PubMed ID: 21900383; Yoshizawa-Ogasawara et al. 2013. PubMed ID: 23457309; Jin et al. 2014. PubMed ID: 25248169). This variant is reported in 0.12% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-45400357-C-T) and is reported as likely pathogenic or pathogenic by many outside laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/225342/). This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Feb 27, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect as the generation of H2O2 was significantly reduced in the G488R transfected cells (PMID: 25248169, 21900383); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27821020, 34200080, 31044655, 21900383, 26709262, 25248169, 30609409, 29650690, 32469330, 32459320, 29092890, 23457309, 32425884, 34426522, 33631011, 33651715, 38373250, 34564849, 39029043) -

Nongoitrous Euthyroid Hyperthyrotropinemia

Pathogenic:1

Jan 01, 2017

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Familial thyroid dyshormonogenesis

Pathogenic:1

Apr 14, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly488Arg (NM014080.4 c.1462G>A) variant in DUOX2 has been reported in 9 h eterozygous, 3 homozygous, and 8 compound heterozygous Asian individuals with cl inical features of congenital hypothyroidism and related disorders (Narumi 2011, Yoshizawa-Ogasawara 2013, Jin 2014, Park 2016, Srichomkwun 2017). This variant has been identified in 0.15% (13/8,652) of East Asian chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs191759494). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro func tional studies provide support that the p.Gly488Arg variant impacts protein func tion (Narumi 2011 and Jin 2015). In summary, this variant meets criteria to be c lassified as pathogenic for congenital hypothyroidism and related disorders in a n autosomal recessive manner based upon biallelic occurrence in affected individ uals, low frequency in control populations, and functional studies. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

T;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.64

D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

3.6

.;H

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.6

D;.

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0060

D;.

Sift4G

Uncertain

0.010

D;D

Polyphen

1.0

.;D

Vest4

0.96

MutPred

0.73

Gain of methylation at G488 (P = 0.0365);Gain of methylation at G488 (P = 0.0365);

MVP

0.93

MPC

0.40

ClinPred

0.83

GERP RS

5.5

Varity_R

0.95

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Other links and lift over