NM_001079668.3(NKX2-1):c.524C>A (p.Ser175Ter) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 20, 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:: RCV000760480.6

Allele description [Variation Report for NM_001079668.3(NKX2-1):c.524C>A (p.Ser175Ter)]

NM_001079668.3(NKX2-1):c.524C>A (p.Ser175Ter)

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.524C>A (p.Ser175Ter)

HGVS:

NC_000014.9:g.36517960G>T
NG_013365.1:g.7266C>A
NM_001079668.3:c.524C>AMANE SELECT
NM_003317.4:c.434C>A
NP_001073136.1:p.Ser175Ter
NP_003308.1:p.Ser145Ter
NC_000014.8:g.36987165G>T
NM_001079668.2:c.524C>A

Protein change:

S145*

Links:

dbSNP: rs863225300

NCBI 1000 Genomes Browser:

rs863225300

Molecular consequence:

NM_001079668.3:c.524C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_003317.4:c.434C>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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gi|12084448|pdb|1DP2|A

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000890369	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 20, 2022)	germline	clinical testing	Citation Link,
SCV003442330	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 23, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18788921, 27066577, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000890369

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Oct 20, 2022)

germline

clinical testing

Citation Link,

SCV003442330

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 23, 2021)

germline

clinical testing

PubMed (3)
[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	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A novel NKX2.1 mutation in a family with hypothyroidism and benign hereditary chorea.

Ferrara AM, De Michele G, Salvatore E, Di Maio L, Zampella E, Capuano S, Del Prete G, Rossi G, Fenzi G, Filla A, Macchia PE.

Thyroid. 2008 Sep;18(9):1005-9. doi: 10.1089/thy.2008.0085.

PubMed [citation]

PMID:: 18788921

Benign hereditary chorea related to NKX2-1 with ataxia and dystonia.

de Gusmao CM, Kok F, Casella EB, Waugh JL.

Neurol Genet. 2016 Feb;2(1):e40. doi: 10.1212/NXG.0000000000000040.

PubMed [citation]

PMID:: 27066577
PMCID:: PMC4817908

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000890369.3

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

Description

Reported in unrelated patients with benign hereditary chorea referred for genetic testing at GeneDx and in the published literature (Ferrara et al., 2008; Salvatore et al., 2010); Nonsense variant predicted to result in protein truncation, as the last 227 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Published functional studies demonstrate p.(S175*) renders the NKX2-1 protein unable to translocate into the nucleus (Ferrara et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24555207, 20544814, 18788921, 27066577)

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003442330.2

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

Description

This sequence change creates a premature translational stop signal (p.Ser175*) in the NKX2-1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 227 amino acid(s) of the NKX2-1 protein. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects NKX2-1 function (PMID: 18788921). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 217884). This variant is also known as c.609C>A (p.S145X). This premature translational stop signal has been observed in individual(s) with NKX2-1 related conditions (PMID: 18788921, 27066577). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).

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

Last Updated: Nov 10, 2024

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