NM_003560.4(PLA2G6):c.439G>A (p.Ala147Thr) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 19, 2021
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:: RCV001584047.1

Allele description [Variation Report for NM_003560.4(PLA2G6):c.439G>A (p.Ala147Thr)]

NM_003560.4(PLA2G6):c.439G>A (p.Ala147Thr)

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.439G>A (p.Ala147Thr)

HGVS:

NC_000022.11:g.38143275C>T
NG_007094.3:g.76504G>A
NM_001004426.3:c.439G>A
NM_001199562.3:c.439G>A
NM_001349864.2:c.439G>A
NM_001349865.2:c.439G>A
NM_001349866.2:c.439G>A
NM_001349867.2:c.-96G>A
NM_001349868.2:c.-52G>A
NM_001349869.2:c.-96G>A
NM_003560.4:c.439G>AMANE SELECT
NP_001004426.1:p.Ala147Thr
NP_001186491.1:p.Ala147Thr
NP_001336793.1:p.Ala147Thr
NP_001336794.1:p.Ala147Thr
NP_001336795.1:p.Ala147Thr
NP_003551.2:p.Ala147Thr
LRG_1015t1:c.439G>A
LRG_1015:g.76504G>A
LRG_1015p1:p.Ala147Thr
NC_000022.10:g.38539282C>T
NG_007094.2:g.67416G>A
NM_003560.2:c.439G>A

Protein change:

A147T

Links:

dbSNP: rs138672490

NCBI 1000 Genomes Browser:

rs138672490

Molecular consequence:

NM_001349867.2:c.-96G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001349868.2:c.-52G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001349869.2:c.-96G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001004426.3:c.439G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001199562.3:c.439G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349864.2:c.439G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349865.2:c.439G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349866.2:c.439G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003560.4:c.439G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001821306	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Aug 19, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27196560, 16783378, 33361639 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001821306

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Aug 19, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic Analysis of PLA2G6 in 22 Indian Families with Infantile Neuroaxonal Dystrophy, Atypical Late-Onset Neuroaxonal Dystrophy and Dystonia Parkinsonism Complex.

Kapoor S, Shah MH, Singh N, Rather MI, Bhat V, Gopinath S, Bindu PS, Taly AB, Sinha S, Nagappa M, Bharath RD, Mahadevan A, Narayanappa G, Chickabasaviah YT, Kumar A.

PLoS One. 2016;11(5):e0155605. doi: 10.1371/journal.pone.0155605.

PubMed [citation]

PMID:: 27196560
PMCID:: PMC4873246

PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron.

Morgan NV, Westaway SK, Morton JE, Gregory A, Gissen P, Sonek S, Cangul H, Coryell J, Canham N, Nardocci N, Zorzi G, Pasha S, Rodriguez D, Desguerre I, Mubaidin A, Bertini E, Trembath RC, Simonati A, Schanen C, Johnson CA, Levinson B, Woods CG, et al.

Nat Genet. 2006 Jul;38(7):752-4. Epub 2006 Jun 18. Erratum in: Nat Genet. 2006 Aug;38(8):957.

PubMed [citation]

PMID:: 16783378
PMCID:: PMC2117328

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001821306.1

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

Description

Variant summary: PLA2G6 c.439G>A (p.Ala147Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 249792 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PLA2G6 causing Neurodegeneration With Brain Iron Accumulation (0.00013 vs 0.00085), allowing no conclusion about variant significance. c.439G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with features of Neurodegeneration With Brain Iron Accumulation such as infantile neuroaxonal dystrophy (INAD) and has been subsequently cited by others (example, Morgan_2006, Kapoor_2016). However, the same compound heterozygous genotype reported in this individual has subsequently been reported in the same chromosome (in cis) of two asymptomatic individuals who had a reported family history of infantile neuroaxonal dystrophy (example, Allouche_2020). The authors concluded that these variants are not responsible for the associated phenotype of autosomal recessive infantile neuroaxonal dystrophy. Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Neurodegeneration With Brain Iron Accumulation and/or INAD. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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: Sep 29, 2024

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