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NM_001243133.2(NLRP3):c.1306A>G (p.Thr436Ala) AND not provided

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 19, 2016
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000433450.1

Allele description [Variation Report for NM_001243133.2(NLRP3):c.1306A>G (p.Thr436Ala)]

NM_001243133.2(NLRP3):c.1306A>G (p.Thr436Ala)

Gene:
NLRP3:NLR family pyrin domain containing 3 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q44
Genomic location:
Preferred name:
NM_001243133.2(NLRP3):c.1306A>G (p.Thr436Ala)
HGVS:
  • NC_000001.11:g.247424755A>G
  • NG_007509.2:g.13583A>G
  • NM_001079821.3:c.1306A>G
  • NM_001127461.3:c.1306A>G
  • NM_001127462.3:c.1306A>G
  • NM_001243133.2:c.1306A>GMANE SELECT
  • NM_004895.5:c.1312A>G
  • NM_183395.3:c.1306A>G
  • NP_001073289.2:p.Thr436Ala
  • NP_001120933.2:p.Thr436Ala
  • NP_001120934.2:p.Thr436Ala
  • NP_001230062.1:p.Thr436Ala
  • NP_001230062.1:p.Thr436Ala
  • NP_004886.3:p.Thr438Ala
  • NP_004886.3:p.Thr438Ala
  • NP_899632.2:p.Thr436Ala
  • LRG_197t1:c.1312A>G
  • LRG_197:g.13583A>G
  • LRG_197p1:p.Thr438Ala
  • NC_000001.10:g.247588057A>G
  • NM_001243133.1:c.1306A>G
  • NM_004895.4:c.1312A>G
Protein change:
T436A
Links:
dbSNP: rs180177465
NCBI 1000 Genomes Browser:
rs180177465
Molecular consequence:
  • NM_001079821.3:c.1306A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127461.3:c.1306A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127462.3:c.1306A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243133.2:c.1306A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004895.5:c.1312A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_183395.3:c.1306A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000512626GeneDx
criteria provided, single submitter

(GeneDx Variant Classification (06012015))		Likely pathogenic
(Dec 19, 2016) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000512626.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The T438A variant has been published previously in association with an NLRP3-associated disorder (Zeft et al., 2007). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. T438A is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the NACHT domain where amino acids with similar properties to Threonine are tolerated across species. The NACHT domain is a known locus for pathogenic variants (Masters et al., 2009), and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, T438A has been reported to impair expression of the NLRP3 protein; however, the authors did not publish their data (Guo et al., 2016). Missense variants in the same residue (T438P/I/N) and in nearby residues (T435I, K437E, A441P/T/V, Y443H) have been reported in the Human Gene Mutation Database in association with NLRP3-associated disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024