NM_199334.5:c.1207G>A

Variant names:

• chr17-40089430-G-A
• rs876657395
• NM_199334.5:c.1207G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_199334.5(THRA):​c.1207G>A​(p.Glu403Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: THRA NM_199334.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.63
• Publications: 3 publications found

Genes affected

THRA (HGNC:11796): (thyroid hormone receptor alpha) The protein encoded by this gene is a nuclear hormone receptor for triiodothyronine. It is one of the several receptors for thyroid hormone, and has been shown to mediate the biological activities of thyroid hormone. Knockout studies in mice suggest that the different receptors, while having certain extent of redundancy, may mediate different functions of thyroid hormone. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

THRA Gene-Disease associations (from GenCC):

• congenital nongoitrous hypothyroidism 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the THRA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.4693 (above the threshold of 3.09). Trascript score misZ: 4.6029 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital nongoitrous hypothyroidism 6.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905
• PP5: Variant 17-40089430-G-A is Pathogenic according to our data. Variant chr17-40089430-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 192272.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
THRA	NM_199334.5	c.1207G>A	p.Glu403Lys	missense_variant	Exon 9 of 9	ENST00000450525.7	NP_955366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRA	ENST00000450525.7	c.1207G>A	p.Glu403Lys	missense_variant	Exon 9 of 9	1	NM_199334.5	ENSP00000395641.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 20, 2023

Molecular Genetics laboratory, Necker Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in individuals with features consistent with THRA-related hypothyroidism in published literature (PMID: 25670821, 33509032); Previously reported as a de novo variant in a proband from a large autism cohort; additional clinical details were not provided, and other de novo variants may have also been present (PMID: 33057194, 35982159); In silico analysis suggests that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33509032, 26812777, 34871063, Marelli2023[Abstract], 33057194, 35982159, 25670821) -

Congenital nongoitrous hypothyroidism 6 Pathogenic:2

May 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 09, 2024

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_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with congenital nongoitrous hypothyroidism 6 (MIM#614450) (PMID: 28932413). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. There can be large variation in the severity of the phenotypes in RTHa as some patients can have mild phenotypes with minimal symptoms (PMID: 28932413). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated coactivator recognition site within the ligand binding domain of thyroid hormone receptor (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least three affected individuals (PMIDs: 26812777, 32349464, 33509032) and classified as pathogenic in ClinVar. (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	.;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	0.97	D
PhyloP100		9.6
PROVEAN	Benign	-2.3	N;N
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.037	D;D
Vest4		0.59
MutPred		0.76		Gain of methylation at E403 (P = 0.0036);Gain of methylation at E403 (P = 0.0036);
MVP		0.96
ClinPred		0.88	D
GERP RS		4.7
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs876657395; hg19: chr17-38245683; COSMIC: COSV52845965; COSMIC: COSV52845965;