NM_003466.4(PAX8):c.322C>T (p.Arg108Ter) AND Hypothyroidism, congenital, nongoitrous, 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 20, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000014793.28

Allele description [Variation Report for NM_003466.4(PAX8):c.322C>T (p.Arg108Ter)]

NM_003466.4(PAX8):c.322C>T (p.Arg108Ter)

Genes:

PAX8-AS1:PAX8 antisense RNA 1 [Gene - HGNC]
PAX8:paired box 8 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q14.1

Genomic location:

Preferred name:

NM_003466.4(PAX8):c.322C>T (p.Arg108Ter)

HGVS:

NC_000002.12:g.113244494G>A
NG_012384.1:g.39428C>T
NM_003466.4:c.322C>TMANE SELECT
NM_013952.4:c.322C>T
NM_013953.4:c.322C>T
NM_013992.4:c.322C>T
NP_003457.1:p.Arg108Ter
NP_039246.1:p.Arg108Ter
NP_039247.1:p.Arg108Ter
NP_054698.1:p.Arg108Ter
NC_000002.11:g.114002071G>A

Protein change:

R108*; ARG108TER

Links:

OMIM: 167415.0002; dbSNP: rs104893655

NCBI 1000 Genomes Browser:

rs104893655

Molecular consequence:

NM_003466.4:c.322C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_013952.4:c.322C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_013953.4:c.322C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_013992.4:c.322C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Hypothyroidism, congenital, nongoitrous, 2 (CHNG2)
Synonyms:: Hypothyroidism, congenital, due to thyroid dysgenesis or hypoplasia
Identifiers:: MONDO: MONDO:0024264; MedGen: C1869118; Orphanet: 95712; OMIM: 218700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000035048	OMIM	no assertion criteria provided	Pathogenic (May 1, 1998)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002579101	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 20, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000035048

OMIM

no assertion criteria provided

Pathogenic
(May 1, 1998)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV002579101

MGZ Medical Genetics Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 20, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis.

Macchia PE, Lapi P, Krude H, Pirro MT, Missero C, Chiovato L, Souabni A, Baserga M, Tassi V, Pinchera A, Fenzi G, Grüters A, Busslinger M, Di Lauro R.

Nat Genet. 1998 May;19(1):83-6.

PubMed [citation]

PMID:: 9590296

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000035048.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In an infant diagnosed with congenital hypothyroidism (CHNG2; 218700) on neonatal screening who was found to have thyroid ectopy and reduced gland size, Macchia et al. (1998) identified heterozygosity for a C-to-T substitution in the first position of codon 108 of the PAX8 gene, changing CGA (arg) to TGA (stop) in exon 3. The nonsense mutation was predicted to result in the synthesis of truncated protein containing only the first 100 amino acids of the paired domain. The mutation was not found in the parents or an unaffected brother, indicating that it was a de novo mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002579101.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

Last Updated: May 7, 2024

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