VCV002444045.3 - ClinVar

NM_001079668.3(NKX2-1):c.464-9C>A

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001079668.3(NKX2-1):c.464-9C>A

Variation ID: 2444045 Accession: VCV002444045.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q13.3 14: 36518029 (GRCh38) [ NCBI UCSC ] 14: 36987234 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 18, 2023	Feb 14, 2024	Jan 2, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001079668.3:c.464-9C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001079668.2:c.464-9C>A
NM_003317.4:c.374-9C>A		intron variant
NC_000014.9:g.36518029G>T
NC_000014.8:g.36987234G>T
NG_013365.1:g.7197C>A
NG_128910.1:g.639G>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000014.9:36518028:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NKX2-1		-	-	GRCh38 GRCh37	2	367
SFTA3		-	-	GRCh38 GRCh37	-	331

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Brain-lung-thyroid syndrome	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 23, 2023	RCV003152843.2
not provided	Pathogenic (1)	criteria provided, single submitter	Jan 2, 2024	RCV003561195.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Brain-lung-thyroid syndrome Affected status: yes Allele origin: unknown	3billion Accession: SCV003841297.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (2) PubMed: 22825795‚ 28588801 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. The variant is an intron variant. In silico tools predict the variant to alter splicing … (more) The variant is not observed in the gnomAD v2.1.1 dataset. The variant is an intron variant. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.87). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 22825795, 28588801). The variant has been reported to be associated with NKX2-1 related disorder (PMID: 22825795). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Motor delay (present)
Pathogenic (Jan 27, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Brain-lung-thyroid syndrome (Autosomal dominant inheritance) Affected status: yes, unknown Allele origin: maternal, unknown	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV003935947.1 First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023	Publications: PubMed (1) PubMed: 22825795 Observation 1: Clinical Features: Hypothyroidism (present) , Hypoxemia (present) , Central apnea (present) Zygosity: Single Heterozygote Age: 0-9 years Sex: female Tissue: blood Observation 2: Clinical Features: Hypothyroidism (present) Zygosity: Single Heterozygote Age: 0-9 years Sex: female Tissue: blood Observation 3: Clinical Features: Hypothyroidism (present) Zygosity: Single Heterozygote Age: 20-29 years Sex: female Tissue: blood Observation 4: Zygosity: Single Heterozygote Age: 20-29 years Sex: female Tissue: blood Observation 5: Clinical Features: Global developmental delay (present) , Chorea (present) , Asthma (present) Zygosity: Single Heterozygote Age: 10-19 years Sex: female Tissue: blood
Pathogenic (Jan 02, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004296335.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 22825795‚ 28588801 Comment: This sequence change falls in intron 2 of the NKX2-1 gene. It does not directly change the encoded amino acid sequence of the NKX2-1 protein. … (more) This sequence change falls in intron 2 of the NKX2-1 gene. It does not directly change the encoded amino acid sequence of the NKX2-1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features consistent with NKX2-1 related conditions (PMID: 22825795, 28588801; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2444045). Studies have shown that this variant results in an out of frame insertion and introduces a premature termination codon (PMID: 22825795). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is an intron variant. In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.87). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 22825795, 28588801). The variant has been reported to be associated with NKX2-1 related disorder (PMID: 22825795). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change falls in intron 2 of the NKX2-1 gene. It does not directly change the encoded amino acid sequence of the NKX2-1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features consistent with NKX2-1 related conditions (PMID: 22825795, 28588801; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2444045). Studies have shown that this variant results in an out of frame insertion and introduces a premature termination codon (PMID: 22825795). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Interstitial lung disease of infancy caused by a new NKX2-1 mutation.	Safi KH	Clinical case reports	2017	PMID: 28588801
Benign hereditary chorea: dopaminergic brain imaging in patients with a novel intronic NKX2.1 gene mutation.	Konishi T	Journal of neurology	2013	PMID: 22825795

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001079668.3(NKX2-1):c.464-9C>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...