rs121908088

Variant names:

• chr2-1494011-C-G
• rs121908088
• NM_001206744.2:c.1978C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-1494011-C-G
• chr2-1494011-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM1 PP5_Very_Strong BP4

The NM_001206744.2(TPO):​c.1978C>G​(p.Gln660Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,614,164 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: TPO NM_001206744.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.24
• Publications: 17 publications found

Genes affected

TPO (HGNC:12015): (thyroid peroxidase) This gene encodes a membrane-bound glycoprotein. The encoded protein acts as an enzyme and plays a central role in thyroid gland function. The protein functions in the iodination of tyrosine residues in thyroglobulin and phenoxy-ester formation between pairs of iodinated tyrosines to generate the thyroid hormones, thyroxine and triiodothyronine. Mutations in this gene are associated with several disorders of thyroid hormonogenesis, including congenital hypothyroidism, congenital goiter, and thyroid hormone organification defect IIA. Multiple transcript variants encoding distinct isoforms have been identified for this gene, but the full-length nature of some variants has not been determined. [provided by RefSeq, May 2011]

TPO Gene-Disease associations (from GenCC):

• thyroid dyshormonogenesis 2A

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000231482 (HGNC:):

ENSG00000228613 (HGNC:58132):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001206744.2
• PP5: Variant 2-1494011-C-G is Pathogenic according to our data. Variant chr2-1494011-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25727427). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPO	NM_001206744.2	c.1978C>G	p.Gln660Glu	missense_variant	Exon 11 of 17	ENST00000329066.9	NP_001193673.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPO	ENST00000329066.9	c.1978C>G	p.Gln660Glu	missense_variant	Exon 11 of 17	1	NM_001206744.2	ENSP00000329869.4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000323 AC: 81 AN: 251150 AF XY: 0.000287

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000327 AC: 478 AN: 1461848 Hom.: 1 Cov.: 33 AF XY: 0.000287 AC XY: 209 AN XY: 727216

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00139 AC: 62 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000359 AC: 399 AN: 1112006

Other (OTH) AF: 0.000232 AC: 14 AN: 60394

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74468

African (AFR) AF: 0.0000962 AC: 4 AN: 41574

American (AMR) AF: 0.000392 AC: 6 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000288 Hom.: 0

Bravo AF: 0.000159

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000346 AC: 42

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of iodide peroxidase Pathogenic:4

May 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TPO c.1978C>G (p.Gln660Glu) missense variant has been reported in at least four studies in which it is found in a total of 25 individuals affected with congenital hypothyroidism from 17 families, including in one in a homozygous state, in 14 in a compound heterozygous state and in 10 with unknown zygosity (Santos et al. 1999; Rodrigues et al. 2005; Deladoey et al. 2008; Al-Faisal et al. 2014). The p.Gln660Glu variant was absent from 75 controls and is reported at a frequency of 0.003326 in the Other population of the Exome Aggregation Consortium. The Gln660 residue is noted to be well conserved. Immunohistochemistry of the thyroid from an affected patient carrying the p.Gln660Glu variant with an anti-TPO antibody revealed a pattern similar to the normal control. However, the substitution of the glutamine residue by a glutamate severely affects the electrostatic potential of the residue generating an altered electrostatic environment around its catalytic site (Deladoey et al. 2008). Based on the collective data, the p.Gln660Glu 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. -

Feb 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 19, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to glutamic acid (exon 11). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (84 heterozygotes, 1 homozygote). (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (An_peroxidase domain; PDB, DECIPHER, NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in several patients with both non-toxic and toxic goiter and congenital hypothyroidism as homozygotes and compound heterzoygotes (ClinVar; PMID: 18029453, 15745925, 10468986) (P) 0901 - Strong evidence for segregation with disease. This variant has been shown to segregate in 5 families (PMID: 18029453, 15745925, 10468986). (P) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided Pathogenic:2

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 660 of the TPO protein (p.Gln660Glu). This variant is present in population databases (rs121908088, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of thyroid dyshormonogenesis (PMID: 10468986, 15745925, 18029453, 24482635, 31430255). It has also been observed to segregate with disease in related individuals. This variant is also known as C to G at position 2068. ClinVar contains an entry for this variant (Variation ID: 4053). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TPO protein function. For these reasons, this variant has been classified as Pathogenic. -

Jan 09, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 28648508, 10468986, 18029453, 24482635, 25968604, 31589614, 31301652, 35995307, 34200080, 31430255, 34211162, 15745925, 34220711, 34248839, 35272499, Jeong2020[paper], 35507000, 36884306) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;.;.;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;.;D;D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	4.6	H;H;.;H;.;.;.
PhyloP100		7.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;.;.
Vest4		0.95
MVP		0.93
MPC		0.70
ClinPred		0.78	D
GERP RS		4.8
Varity_R		0.94
gMVP		0.98
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908088; hg19: chr2-1497783;