NM_001079668.3(NKX2-1):c.626G>C (p.Arg209Pro) AND Brain-lung-thyroid syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: May 24, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002466760.4

Allele description [Variation Report for NM_001079668.3(NKX2-1):c.626G>C (p.Arg209Pro)]

NM_001079668.3(NKX2-1):c.626G>C (p.Arg209Pro)

Genes:

NKX2-1:NK2 homeobox 1 [Gene - OMIM - HGNC]
SFTA3:surfactant associated 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q13.3

Genomic location:

Preferred name:

NM_001079668.3(NKX2-1):c.626G>C (p.Arg209Pro)

HGVS:

NC_000014.9:g.36517858C>G
NG_013365.1:g.7368G>C
NM_001079668.2:c.626G>C
NM_001079668.3:c.626G>CMANE SELECT
NM_003317.4:c.536G>C
NP_001073136.1:p.Arg209Pro
NP_003308.1:p.Arg179Pro
NC_000014.8:g.36987063C>G

Protein change:

R179P

Molecular consequence:

NM_001079668.3:c.626G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_003317.4:c.536G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Brain-lung-thyroid syndrome
Synonyms:: Choreoathetosis, hypothyroidism, and neonatal respiratory distress; CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH PULMONARY DYSFUNCTION
Identifiers:: MONDO: MONDO:0012593; MedGen: C1970269; Orphanet: 209905; OMIM: 610978

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002762679	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Likely pathogenic (May 24, 2022)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24453141, 29109906 Citation Link,
SCV003935961	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 28, 2020)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24453141, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002762679

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)

Likely pathogenic
(May 24, 2022)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV003935961

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 28, 2020)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	1	yes	clinical testing

Citations

PubMed

The Movement Disorder of Brain-Lung-Thyroid Syndrome Can be Responsive to Methylphenidate.

Gauquelin L, Tran LT, Chouinard S, Bernard G.

Tremor Other Hyperkinet Mov (N Y). 2017;7:508. doi: 10.7916/D84X5M9Z. No abstract available.

PubMed [citation]

PMID:: 29109906
PMCID:: PMC5666014

A novel mutation of NKX2-1 affecting 2 generations with hypothyroidism and choreoathetosis: part of the spectrum of brain-thyroid-lung syndrome.

Williamson S, Kirkpatrick M, Greene S, Goudie D.

J Child Neurol. 2014 May;29(5):666-9. doi: 10.1177/0883073813518243. Epub 2014 Jan 21.

PubMed [citation]

PMID:: 24453141

See all PubMed Citations (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV002762679.1

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

Description

The NKX2-1 c.626G>C (p.Arg209Pro) missense variant results in the substitution of arginine at amino acid position 209 with proline. This variant has been reported in a total of two unrelated families with choreoathetosis, hypothyroidism, and neonatal respiratory distress (also referred to brain-thyroid-lung syndrome) in a heterozygous state (Williamson et al. 2014; Guaquelin et al. 2017). In one family the variant was present in two brothers with the condition as well as in the affected daughter of one of the brothers (Williamson et al. 2014). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Based on the available evidence, the c.626G>C (p.Arg209Pro) variant is classified as likely pathogenic for choreoathetosis, hypothyroidism, and neonatal respiratory distress.

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

From Molecular Diagnostics Lab, Nemours Children's Health, Delaware, SCV003935961.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	yes	clinical testing (GTR000334192.3)	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	blood	not provided	(GTR000334192.3)	1	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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