NM_001079668.3(NKX2-1):c.1045dup (p.His349fs) AND Brain-lung-thyroid syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Sep 3, 2025
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:: RCV003237287.3

Allele description [Variation Report for NM_001079668.3(NKX2-1):c.1045dup (p.His349fs)]

NM_001079668.3(NKX2-1):c.1045dup (p.His349fs)

Genes:

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

Variant type:

Duplication

Cytogenetic location:

14q13.3

Genomic location:

Preferred name:

NM_001079668.3(NKX2-1):c.1045dup (p.His349fs)

HGVS:

NC_000014.9:g.36517440dup
NG_013365.1:g.7787dup
NG_128910.1:g.50dup
NM_001079668.3:c.1045dupMANE SELECT
NM_003317.4:c.955dup
NP_001073136.1:p.His349fs
NP_003308.1:p.His319fs
NC_000014.8:g.36986645dup
NM_001079668.2:c.1045dupC

Protein change:

H319fs

Links:

dbSNP: rs2502626171

NCBI 1000 Genomes Browser:

rs2502626171

Molecular consequence:

NM_001079668.3:c.1045dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_003317.4:c.955dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Brain-lung-thyroid syndrome
Synonyms:: CHOREOATHETOSIS AND CONGENITAL HYPOTHYROIDISM WITH PULMONARY DYSFUNCTION; Choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress
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
SCV003935933	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 11, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV006556014	Clinical Genomics Laboratory, Washington University in St. Louis	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 3, 2025)	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

SCV003935933

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 11, 2020)

unknown

clinical testing

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

SCV006556014

Clinical Genomics Laboratory, Washington University in St. Louis

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 3, 2025)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

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 Molecular Diagnostics Lab, Nemours Children's Health, Delaware, SCV003935933.2

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

#	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

From Clinical Genomics Laboratory, Washington University in St. Louis, SCV006556014.1

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

Description

The NKX2-1 c.1045dup (p.His349Profs*90) variant, to our knowledge, has not been reported in the medical literature but has been reported in the ClinVar database as a likely pathogenic variant by one submitter. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a frameshift by duplicating a single nucleotide, leading to a premature termination codon; however, because this occurs in the last exon, this is not predicted to lead to nonsense-mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

#	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		not provided	not provided	not provided	not provided

Last Updated: Oct 18, 2025

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Relating variation to medicine