VCV003362281.1 - ClinVar

NM_000169.3(GLA):c.23T>A (p.Leu8Gln)

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.

(1)

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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000169.3(GLA):c.23T>A (p.Leu8Gln)

Variation ID: 3362281 Accession: VCV003362281.1

Type and length

single nucleotide variant, -

Location

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	Oct 13, 2024	Oct 13, 2024	May 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000169.3:c.23T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000160.1:p.Leu8Gln	missense
NM_001199973.2:c.301-4055A>T		intron variant
NM_001199974.2:c.178-4055A>T		intron variant
NM_001406747.1:c.23T>A	NP_001393676.1:p.Leu8Gln	missense
NM_001406748.1:c.23T>A	NP_001393677.1:p.Leu8Gln	missense
NM_001406749.1:c.23T>A	NP_001393678.1:p.Leu8Gln	missense
NR_164783.1:n.45T>A		non-coding transcript variant
NR_176252.1:n.45T>A		non-coding transcript variant
NR_176253.1:n.45T>A		non-coding transcript variant
NC_000023.11:g.101407881A>T
NC_000023.10:g.100662869A>T
NG_007119.1:g.5083T>A
NG_016327.1:g.4679A>T
LRG_672:g.5083T>A
LRG_672t1:c.23T>A	LRG_672p1:p.Leu8Gln

... more HGVS ... less HGVS

Protein change

L8Q

Other names

Canonical SPDI

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.

Links

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.
GLA		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	7	1257

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.
Fabry disease	Pathogenic (1)	criteria provided, single submitter	May 20, 2023	RCV004764288.1

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.
Pathogenic (May 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fabry disease (X-linked inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005373551.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: The missense variant c.139G>A(p.Gly47Arg) in ADA2 gene has been has been observed in compound heterozygous state in multiple individuals with ADA2 deficiency and polyarteritis nodosa … (more) The missense variant c.139G>A(p.Gly47Arg) in ADA2 gene has been has been observed in compound heterozygous state in multiple individuals with ADA2 deficiency and polyarteritis nodosa (Skrabl-Baumgartner et. al., 2017; Caorsi et. al., 2017). It has also been observed to segregate with disease in related individuals. Experimental studies have shown that this missense change affects ADA2 function (Navon et. al., 2014). This variant disrupts the p.Gly47 amino acid residue in ADA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Günthner et. al., 2018). The observed variant has alllele frequency of 0.01% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change p.Gly47Arg in ADA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 47 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Abnormality of the nervous system (present)

Comment:

The missense variant c.139G>A(p.Gly47Arg) in ADA2 gene has been has been observed in compound heterozygous state in multiple individuals with ADA2 deficiency and polyarteritis nodosa (Skrabl-Baumgartner et. al., 2017; Caorsi et. al., 2017). It has also been observed to segregate with disease in related individuals. Experimental studies have shown that this missense change affects ADA2 function (Navon et. al., 2014). This variant disrupts the p.Gly47 amino acid residue in ADA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Günthner et. al., 2018). The observed variant has alllele frequency of 0.01% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change p.Gly47Arg in ADA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 47 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000169.3(GLA):c.23T>A (p.Leu8Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...