VCV000493345.22 - ClinVar

NM_003560.4(PLA2G6):c.16C>T (p.Arg6Cys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(10)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003560.4(PLA2G6):c.16C>T (p.Arg6Cys)

Variation ID: 493345 Accession: VCV000493345.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q13.1 22: 38169411 (GRCh38) [ NCBI UCSC ] 22: 38565418 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 3, 2018	May 1, 2024	Aug 23, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_003560.4:c.16C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003551.2:p.Arg6Cys	missense
NM_001004426.3:c.16C>T	NP_001004426.1:p.Arg6Cys	missense
NM_001199562.3:c.16C>T	NP_001186491.1:p.Arg6Cys	missense
NM_001349864.2:c.16C>T	NP_001336793.1:p.Arg6Cys	missense
NM_001349865.2:c.16C>T	NP_001336794.1:p.Arg6Cys	missense
NM_001349866.2:c.16C>T	NP_001336795.1:p.Arg6Cys	missense
NM_001349867.2:c.-650C>T		5 prime UTR
NM_001349868.2:c.-475C>T		5 prime UTR
NM_001349869.2:c.-650C>T		5 prime UTR
NM_003560.3:c.16C>T
NC_000022.11:g.38169411G>A
NC_000022.10:g.38565418G>A
NG_007094.3:g.50368C>T
LRG_1015:g.50368C>T
LRG_1015t1:c.16C>T	LRG_1015p1:p.Arg6Cys

... more HGVS ... less HGVS

Protein change

R6C

Other names

p.Arg6Cys

Canonical SPDI

NC_000022.11:38169410:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00012

The Genome Aggregation Database (gnomAD), exomes 0.00012

Exome Aggregation Consortium (ExAC) 0.00014

Trans-Omics for Precision Medicine (TOPMed) 0.00015

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023

Links

ClinGen: CA10231391 dbSNP: rs143250889 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PLA2G6		-	-	GRCh38 GRCh37	1068	1100

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Jul 14, 2021	RCV000584924.12
Autosomal recessive Parkinson disease 14 Infantile neuroaxonal dystrophy Neurodegeneration with brain iron accumulation 2B	Uncertain significance (2)	criteria provided, single submitter	Oct 31, 2018	RCV000764385.3
PLA2G6-associated neurodegeneration	Uncertain significance (1)	criteria provided, single submitter	Jan 12, 2018	RCV001144725.4
Infantile neuroaxonal dystrophy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 23, 2022	RCV001231034.7
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Jun 27, 2022	RCV002530854.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile neuroaxonal dystrophy Neurodegeneration with brain iron accumulation 2B Autosomal recessive Parkinson disease 14 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000895438.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Jul 05, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Infantile neuroaxonal dystrophy Affected status: yes Allele origin: inherited	Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences Additional submitter: Children’s Center Hospital, Tehran University of Medical Sciences Accession: SCV001244664.1 First in ClinVar: Oct 25, 2020 Last updated: Oct 25, 2020	Sex: male
Uncertain significance (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	PLA2G6-associated neurodegeneration Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001305338.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jul 14, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001871056.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)
Uncertain significance (Jul 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002541726.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Uncertain significance (Oct 31, 2017)	criteria provided, single submitter (Praxis fuer Humangenetik Tuebingen - Variant Classification Criteria) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000693089.4 First in ClinVar: Mar 03, 2018 Last updated: Dec 24, 2022	Number of individuals with the variant: 2
Uncertain significance (Aug 23, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Infantile neuroaxonal dystrophy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001403537.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 33547378 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 6 of the PLA2G6 protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 6 of the PLA2G6 protein (p.Arg6Cys). This variant is present in population databases (rs143250889, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of leukodystrophy or leukoencephalopathy (PMID: 33547378). ClinVar contains an entry for this variant (Variation ID: 493345). 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. 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. (less)
Uncertain significance (Aug 12, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003808503.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Jun 27, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003696408.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 33547378 Comment: The c.16C>T (p.R6C) alteration is located in exon 2 (coding exon 1) of the PLA2G6 gene. This alteration results from a C to T substitution … (more) The c.16C>T (p.R6C) alteration is located in exon 2 (coding exon 1) of the PLA2G6 gene. This alteration results from a C to T substitution at nucleotide position 16, causing the arginine (R) at amino acid position 6 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (-)	no assertion criteria provided Method: research	Infantile neuroaxonal dystrophy Neurodegeneration with brain iron accumulation 2B Autosomal recessive Parkinson disease 14 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Coban-Akdemir Lab, University of Texas Health Science Center Accession: SCV004231753.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Sex: female Comment on evidence: The affected individual shows increased deep tendon reflexes, spasticity, hirsutism, and severe neurodevelopmental delay. The variant was previously reported in another patient with hypotonia, bristled … (more) The affected individual shows increased deep tendon reflexes, spasticity, hirsutism, and severe neurodevelopmental delay. The variant was previously reported in another patient with hypotonia, bristled hair, and seizure (PMID: 33547378). (less)

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 6 of the PLA2G6 protein (p.Arg6Cys). This variant is present in population databases (rs143250889, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of leukodystrophy or leukoencephalopathy (PMID: 33547378). ClinVar contains an entry for this variant (Variation ID: 493345). 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. 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.

Comment:

The c.16C>T (p.R6C) alteration is located in exon 2 (coding exon 1) of the PLA2G6 gene. This alteration results from a C to T substitution at nucleotide position 16, causing the arginine (R) at amino acid position 6 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic testing of leukodystrophies unraveling extensive heterogeneity in a large cohort and report of five common diseases and 38 novel variants.	Mahdieh N	Scientific reports	2021	PMID: 33547378

Text-mined citations for rs143250889 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_003560.4(PLA2G6):c.16C>T (p.Arg6Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs143250889 ...