VCV000180832.17 - ClinVar

NM_000169.3(GLA):c.1085C>T (p.Pro362Leu)

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.

(5)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000169.3(GLA):c.1085C>T (p.Pro362Leu)

Variation ID: 180832 Accession: VCV000180832.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq22.1 X: 101398014 (GRCh38) [ NCBI UCSC ] X: 100653002 (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	May 29, 2016	Feb 14, 2024	Oct 3, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000169.3:c.1085C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000160.1:p.Pro362Leu	missense
NM_001199973.2:c.300+2557G>A		intron variant
NM_001199974.2:c.177+6192G>A		intron variant
NM_001406747.1:c.1208C>T	NP_001393676.1:p.Pro403Leu	missense
NR_164783.1:n.1164C>T		non-coding transcript variant
NR_176252.1:n.1015C>T		non-coding transcript variant
NR_176253.1:n.1222C>T		non-coding transcript variant
NC_000023.11:g.101398014G>A
NC_000023.10:g.100653002G>A
NG_007119.1:g.14950C>T
LRG_672:g.14950C>T
LRG_672t1:c.1085C>T	LRG_672p1:p.Pro362Leu

... more HGVS ... less HGVS

Protein change

P362L, P403L

Other names

p.P362L:CCT>CTT

Canonical SPDI

NC_000023.11:101398013: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.

Links

ClinGen: CA021367 dbSNP: rs730880441 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.
GLA		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	7	1257
RPL36A-HNRNPH2	-	-	-	GRCh38 GRCh37	-	1295

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	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 18, 2023	RCV000157883.15
Fabry disease	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 3, 2023	RCV001807105.9

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.
Likely pathogenic (Jul 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fabry disease Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002054793.1 First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022
Likely pathogenic (May 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004238216.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Likely pathogenic (Jun 02, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000207814.11 First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023	Comment: Reported in one carrier female from a family with classic Fabry disease; however, details on affected male relatives were not provided (Shabbeer et al., 2002; … (more) Reported in one carrier female from a family with classic Fabry disease; however, details on affected male relatives were not provided (Shabbeer et al., 2002; Shabbeer et al., 2005); Also reported in an adult female with long-term hematuria with good renal function and cornea verticillata, but this variant was also identified in the individual's mother and sister who were reported to be asymptomatic and no male relatives were evaluated (Maixnerov et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant resulted in significant reductions of alpha-galactosidase enzyme activities in HEK293 cells (Benjamin et al., 2017); This variant is associated with the following publications: (PMID: 25382311, 15712228, 23305247, 27657681, 12175777, 28615118) (less)
Pathogenic (Oct 03, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Fabry disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002309122.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 12175777‚ 23305247‚ 27657681 Comment: This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 362 of the GLA protein (p.Pro362Leu). … (more) This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 362 of the GLA protein (p.Pro362Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Fabry disease (PMID: 12175777, 23305247; Invitae). ClinVar contains an entry for this variant (Variation ID: 180832). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLA protein function. Experimental studies have shown that this missense change affects GLA function (PMID: 27657681). For these reasons, this variant has been classified as Pathogenic. (less)
Uncertain significance (Apr 13, 2017)	Flagged submission flagged submission (EGL Classification Definitions 2015) Method: clinical testing Reason: Older and outlier claim with insufficient supporting evidence Source: ClinGen	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000707788.2 First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 12175777 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA Number of individuals with the variant: 2 Sex: mixed
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

Reported in one carrier female from a family with classic Fabry disease; however, details on affected male relatives were not provided (Shabbeer et al., 2002; Shabbeer et al., 2005); Also reported in an adult female with long-term hematuria with good renal function and cornea verticillata, but this variant was also identified in the individual's mother and sister who were reported to be asymptomatic and no male relatives were evaluated (Maixnerov et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant resulted in significant reductions of alpha-galactosidase enzyme activities in HEK293 cells (Benjamin et al., 2017); This variant is associated with the following publications: (PMID: 25382311, 15712228, 23305247, 27657681, 12175777, 28615118)

Comment:

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 362 of the GLA protein (p.Pro362Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Fabry disease (PMID: 12175777, 23305247; Invitae). ClinVar contains an entry for this variant (Variation ID: 180832). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLA protein function. Experimental studies have shown that this missense change affects GLA function (PMID: 27657681). 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

Title	Author	Journal	Year	Link
The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat.	Benjamin ER	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27657681
The coincidence of IgA nephropathy and Fabry disease.	Maixnerová D	BMC nephrology	2013	PMID: 23305247
Fabry disease: 45 novel mutations in the alpha-galactosidase A gene causing the classical phenotype.	Shabbeer J	Molecular genetics and metabolism	2002	PMID: 12175777
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA	-	-	-	-

Text-mined citations for rs730880441 ...

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_000169.3(GLA):c.1085C>T (p.Pro362Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs730880441 ...