NM_001079668.3(NKX2-1):c.872C>T (p.Pro291Leu) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Aug 11, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000415944.28

Allele description [Variation Report for NM_001079668.3(NKX2-1):c.872C>T (p.Pro291Leu)]

NM_001079668.3(NKX2-1):c.872C>T (p.Pro291Leu)

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.872C>T (p.Pro291Leu)

HGVS:

NC_000014.9:g.36517612G>A
NG_013365.1:g.7614C>T
NM_001079668.3:c.872C>TMANE SELECT
NM_003317.4:c.782C>T
NP_001073136.1:p.Pro291Leu
NP_003308.1:p.Pro261Leu
NC_000014.8:g.36986817G>A
NM_001079668.2:c.872C>T

Protein change:

P261L

Links:

dbSNP: rs1057519223

NCBI 1000 Genomes Browser:

rs1057519223

Molecular consequence:

NM_001079668.3:c.872C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003317.4:c.782C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000493634	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Apr 1, 2017)	germline	clinical testing	Citation Link,
SCV002504265	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 21, 2022)	germline	clinical testing	Citation Link,
SCV004296334	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 11, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24171694, 30352709, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000493634

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Likely pathogenic
(Apr 1, 2017)

germline

clinical testing

Citation Link,

SCV002504265

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Apr 21, 2022)

germline

clinical testing

Citation Link,

SCV004296334

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 11, 2023)

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	2	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

Benign hereditary chorea related to NKX2.1: expansion of the genotypic and phenotypic spectrum.

Peall KJ, Lumsden D, Kneen R, Madhu R, Peake D, Gibbon F, Lewis H, Hedderly T, Meyer E, Robb SA, Lynch B, King MD, Lin JP, Morris HR, Jungbluth H, Kurian MA.

Dev Med Child Neurol. 2014 Jul;56(7):642-8. doi: 10.1111/dmcn.12323. Epub 2013 Oct 31.

PubMed [citation]

PMID:: 24171694

Restless Legs Syndrome in NKX2-1-related chorea: An expansion of the disease spectrum.

Iodice A, Carecchio M, Zorzi G, Garavaglia B, Spagnoli C, Salerno GG, Frattini D, Mencacci NE, Invernizzi F, Veneziano L, Mantuano E, Angriman M, Fusco C.

Brain Dev. 2019 Mar;41(3):250-256. doi: 10.1016/j.braindev.2018.10.001. Epub 2018 Oct 21. Erratum in: Brain Dev. 2019 Aug;41(7):643. doi: 10.1016/j.braindev.2019.04.011.

PubMed [citation]

PMID:: 30352709

See all PubMed Citations (3)

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV000493634.32

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

#	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

From GeneDx, SCV002504265.2

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

Description

Identified in a patient with chorea, hypotonia, and neonatal respiratory distress in published literature (Peall et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24171694)

#	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, SCV004296334.1

#	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 replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 291 of the NKX2-1 protein (p.Pro291Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NKX2-1-related conditions (PMID: 24171694). ClinVar contains an entry for this variant (Variation ID: 374740). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Pro291 amino acid residue in NKX2-1. Other variant(s) that disrupt this residue have been observed in individuals with NKX2-1-related conditions (PMID: 30352709), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Oct 8, 2024

ClinVar

Relating variation to medicine