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NM_003560.4(PLA2G6):c.1982C>T (p.Thr661Met) AND Infantile neuroaxonal dystrophy

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Apr 19, 2024
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:
RCV003508541.3

Allele description [Variation Report for NM_003560.4(PLA2G6):c.1982C>T (p.Thr661Met)]

NM_003560.4(PLA2G6):c.1982C>T (p.Thr661Met)

Gene:
PLA2G6:phospholipase A2 group VI [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
22q13.1
Genomic location:
Preferred name:
NM_003560.4(PLA2G6):c.1982C>T (p.Thr661Met)
HGVS:
  • NC_000022.11:g.38115579G>A
  • NG_007094.3:g.104200C>T
  • NG_033059.2:g.91C>T
  • NM_001004426.3:c.1820C>T
  • NM_001199562.3:c.1820C>T
  • NM_001349864.2:c.1982C>T
  • NM_001349865.2:c.1820C>T
  • NM_001349866.2:c.1820C>T
  • NM_001349867.2:c.1448C>T
  • NM_001349868.2:c.1304C>T
  • NM_001349869.2:c.1286C>T
  • NM_003560.4:c.1982C>TMANE SELECT
  • NP_001004426.1:p.Thr607Met
  • NP_001186491.1:p.Thr607Met
  • NP_001336793.1:p.Thr661Met
  • NP_001336794.1:p.Thr607Met
  • NP_001336795.1:p.Thr607Met
  • NP_001336796.1:p.Thr483Met
  • NP_001336797.1:p.Thr435Met
  • NP_001336798.1:p.Thr429Met
  • NP_003551.2:p.Thr661Met
  • LRG_1015t1:c.1982C>T
  • LRG_1015:g.104200C>T
  • LRG_1015p1:p.Thr661Met
  • NC_000022.10:g.38511586G>A
Protein change:
T429M
Molecular consequence:
  • NM_001004426.3:c.1820C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001199562.3:c.1820C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001349864.2:c.1982C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001349865.2:c.1820C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001349866.2:c.1820C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001349867.2:c.1448C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001349868.2:c.1304C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001349869.2:c.1286C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003560.4:c.1982C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Infantile neuroaxonal dystrophy (NBIA2A)
Synonyms:
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 2A; Seitelberger disease; Infantile neuroaxonal dystrophy 1
Identifiers:
MONDO: MONDO:0024457; MedGen: C0270724; Orphanet: 35069; OMIM: 256600

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004281220Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 11, 2024) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV005077195Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Apr 19, 2024) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Clinical exome sequencing as the first-tier test for diagnosing developmental disorders covering both CNV and SNV: a Chinese cohort.

Dong X, Liu B, Yang L, Wang H, Wu B, Liu R, Chen H, Chen X, Yu S, Chen B, Wang S, Xu X, Zhou W, Lu Y.

J Med Genet. 2020 Aug;57(8):558-566. doi: 10.1136/jmedgenet-2019-106377. Epub 2020 Jan 31.

PubMed [citation]
PMID:
32005694
PMCID:
PMC7418612
See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004281220.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 661 of the PLA2G6 protein (p.Thr661Met). This variant is present in population databases (rs767689496, gnomAD 0.006%). This missense change has been observed in individual(s) with infantile neuroaxonal dystrophy (PMID: 23749988, 31069529, 32005694, 35032046). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PLA2G6 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005077195.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Variant summary: PLA2G6 c.1982C>T (p.Thr661Met) results in a non-conservative amino acid change located in the Patatin-like phospholipase domain (IPR002641) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249664 control chromosomes. c.1982C>T has been reported in the literature in multiple individuals affected with Infantile Neuroaxonal Dystrophy, Neurodegeneration with brain iron accumulation and related disorders (Sukenik-Halevy_2022, Koroglu_2012, Arslan_2020, Dong_2020, Ganapathy_2019, Sait_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31493945, 32005694, 31069529, 23749988, 36790591, 35032046). ClinVar contains an entry for this variant (Variation ID: 2724426). Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Sep 29, 2024