In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); Identified in a female patient with left bundle branch block aberrancy who also harbored variants in the NKX2-5 and ALMS1 genes (Kohli et al., 2021); This variant is associated with the following publications: (PMID: 33835496)
ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.1181T>C (p.Leu394Pro)
Germline
Classification
Help
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)
Help
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
10
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.1181T>C (p.Leu394Pro)
Variation ID: 281678 Accession: VCV000281678.26
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq22.1 X: 101397918 (GRCh38) [ NCBI UCSC ] X: 100652906 (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 Dec 6, 2016 May 1, 2024 Jan 3, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000169.3:c.1181T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Leu394Pro missense NM_001199973.2:c.300+2461A>G intron variant NM_001199974.2:c.177+6096A>G intron variant NM_001406747.1:c.1304T>C NP_001393676.1:p.Leu435Pro missense NR_164783.1:n.1260T>C non-coding transcript variant NR_176252.1:n.1111T>C non-coding transcript variant NR_176253.1:n.1318T>C non-coding transcript variant NC_000023.11:g.101397918A>G NC_000023.10:g.100652906A>G NG_007119.1:g.15046T>C LRG_672:g.15046T>C LRG_672t1:c.1181T>C LRG_672p1:p.Leu394Pro - Protein change
- L394P, L435P
- Other names
- -
- Canonical SPDI
- NC_000023.11:101397917:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00002
- 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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 10, 2022 | RCV000316758.10 | |
| Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 3, 2024 | RCV001183037.17 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 26, 2020 | RCV002328756.3 |
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
(Jun 22, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000332577.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 4
Sex: mixed
|
|
|
Uncertain significance
(Jul 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002054340.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
|
|
|
Uncertain significance
(Nov 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002776640.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Uncertain significance
(Jun 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001982529.3
First in ClinVar: Oct 30, 2021 Last updated: Mar 04, 2023 |
Comment:
In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); Identified in a female … (more)
In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); Identified in a female patient with left bundle branch block aberrancy who also harbored variants in the NKX2-5 and ALMS1 genes (Kohli et al., 2021); This variant is associated with the following publications: (PMID: 33835496) (less)
|
|
|
Uncertain significance
(Nov 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003816826.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Uncertain significance
(Dec 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001348687.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces leucine with proline at codon 394 of the GLA protein. Computational prediction tools indicate that this variant's impact on protein structure … (more)
This missense variant replaces leucine with proline at codon 394 of the GLA protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies investigating the impact of this variant on GLA enzyme activity have not been reported. This variant has been reported in a female affected with Fabry disease (PMID: 32719972), in a child with unspecified gender affected with Fabry disease (PMID: 33073010), and in an individual affected with isolated left bundle branch block (PMID: 33835496). However, the variant has been reported in males lacking Fabry disease symptoms in multiple pedigrees affected with kidney disease (doi:10.1101/2022.09.27.509714; not peer-reviewed), suggesting that the variant may not be causative for Fabry disease. This variant has also been observed in additional individuals unaffected with Fabry disease and has not been observed in affected individuals (communication with external laboratories; ClinVar SCV ID: SCV001513189.3, SCV001982529.3, SCV003816826.1; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Dec 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001513189.4
First in ClinVar: Mar 14, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 394 of the GLA protein (p.Leu394Pro). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 394 of the GLA protein (p.Leu394Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GLA-related conditions. ClinVar contains an entry for this variant (Variation ID: 281678). 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 not expected to disrupt GLA protein function with a negative predictive value of 80%. 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
(Jan 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Fabry disease
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004838990.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces leucine with proline at codon 394 of the GLA protein. Computational prediction tools indicate that this variant's impact on protein structure … (more)
This missense variant replaces leucine with proline at codon 394 of the GLA protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies investigating the impact of this variant on GLA enzyme activity have not been reported. This variant has been reported in a female affected with Fabry disease (PMID: 32719972), in a child with unspecified gender affected with Fabry disease (PMID: 33073010), and in an individual affected with isolated left bundle branch block (PMID: 33835496). However, the variant has been reported in males lacking Fabry disease symptoms in multiple pedigrees affected with kidney disease (doi:10.1101/2022.09.27.509714; not peer-reviewed), suggesting that the variant may not be causative for Fabry disease. This variant has also been observed in additional individuals unaffected with Fabry disease and has not been observed in affected individuals (communication with external laboratories; ClinVar SCV ID: SCV001513189.3, SCV001982529.3, SCV003816826.1; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Mar 26, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002634485.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.L394P variant (also known as c.1181T>C), located in coding exon 7 of the GLA gene, results from a T to C substitution at nucleotide … (more)
The p.L394P variant (also known as c.1181T>C), located in coding exon 7 of the GLA gene, results from a T to C substitution at nucleotide position 1181. The leucine at codon 394 is replaced by proline, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Sep 27, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Fabry disease
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002081331.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
This missense variant replaces leucine with proline at codon 394 of the GLA protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies investigating the impact of this variant on GLA enzyme activity have not been reported. This variant has been reported in a female affected with Fabry disease (PMID: 32719972), in a child with unspecified gender affected with Fabry disease (PMID: 33073010), and in an individual affected with isolated left bundle branch block (PMID: 33835496). However, the variant has been reported in males lacking Fabry disease symptoms in multiple pedigrees affected with kidney disease (doi:10.1101/2022.09.27.509714; not peer-reviewed), suggesting that the variant may not be causative for Fabry disease. This variant has also been observed in additional individuals unaffected with Fabry disease and has not been observed in affected individuals (communication with external laboratories; ClinVar SCV ID: SCV001513189.3, SCV001982529.3, SCV003816826.1; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 394 of the GLA protein (p.Leu394Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GLA-related conditions. ClinVar contains an entry for this variant (Variation ID: 281678). 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 not expected to disrupt GLA protein function with a negative predictive value of 80%. 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:
This missense variant replaces leucine with proline at codon 394 of the GLA protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies investigating the impact of this variant on GLA enzyme activity have not been reported. This variant has been reported in a female affected with Fabry disease (PMID: 32719972), in a child with unspecified gender affected with Fabry disease (PMID: 33073010), and in an individual affected with isolated left bundle branch block (PMID: 33835496). However, the variant has been reported in males lacking Fabry disease symptoms in multiple pedigrees affected with kidney disease (doi:10.1101/2022.09.27.509714; not peer-reviewed), suggesting that the variant may not be causative for Fabry disease. This variant has also been observed in additional individuals unaffected with Fabry disease and has not been observed in affected individuals (communication with external laboratories; ClinVar SCV ID: SCV001513189.3, SCV001982529.3, SCV003816826.1; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.L394P variant (also known as c.1181T>C), located in coding exon 7 of the GLA gene, results from a T to C substitution at nucleotide position 1181. The leucine at codon 394 is replaced by proline, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, 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:
In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); Identified in a female patient with left bundle branch block aberrancy who also harbored variants in the NKX2-5 and ALMS1 genes (Kohli et al., 2021); This variant is associated with the following publications: (PMID: 33835496)
Comment:
This missense variant replaces leucine with proline at codon 394 of the GLA protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies investigating the impact of this variant on GLA enzyme activity have not been reported. This variant has been reported in a female affected with Fabry disease (PMID: 32719972), in a child with unspecified gender affected with Fabry disease (PMID: 33073010), and in an individual affected with isolated left bundle branch block (PMID: 33835496). However, the variant has been reported in males lacking Fabry disease symptoms in multiple pedigrees affected with kidney disease (doi:10.1101/2022.09.27.509714; not peer-reviewed), suggesting that the variant may not be causative for Fabry disease. This variant has also been observed in additional individuals unaffected with Fabry disease and has not been observed in affected individuals (communication with external laboratories; ClinVar SCV ID: SCV001513189.3, SCV001982529.3, SCV003816826.1; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 394 of the GLA protein (p.Leu394Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GLA-related conditions. ClinVar contains an entry for this variant (Variation ID: 281678). 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 not expected to disrupt GLA protein function with a negative predictive value of 80%. 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:
This missense variant replaces leucine with proline at codon 394 of the GLA protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies investigating the impact of this variant on GLA enzyme activity have not been reported. This variant has been reported in a female affected with Fabry disease (PMID: 32719972), in a child with unspecified gender affected with Fabry disease (PMID: 33073010), and in an individual affected with isolated left bundle branch block (PMID: 33835496). However, the variant has been reported in males lacking Fabry disease symptoms in multiple pedigrees affected with kidney disease (doi:10.1101/2022.09.27.509714; not peer-reviewed), suggesting that the variant may not be causative for Fabry disease. This variant has also been observed in additional individuals unaffected with Fabry disease and has not been observed in affected individuals (communication with external laboratories; ClinVar SCV ID: SCV001513189.3, SCV001982529.3, SCV003816826.1; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.L394P variant (also known as c.1181T>C), located in coding exon 7 of the GLA gene, results from a T to C substitution at nucleotide position 1181. The leucine at codon 394 is replaced by proline, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Isolated left bundle branch block in the young: case reports and review of literature. | Kohli U | Pacing and clinical electrophysiology : PACE | 2021 | PMID: 33835496 |
| Introducing and Expanding Newborn Screening in the MENA Region. | Skrinska V | International journal of neonatal screening | 2020 | PMID: 33073010 |
| Oxidative stress biomarkers in Fabry disease: is there a room for them? | Simoncini C | Journal of neurology | 2020 | PMID: 32719972 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA | - | - | - | - |
Text-mined citations for rs886044779 ...
HelpThese 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
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.