ClinVar Genomic variation as it relates to human health
NM_013247.5(HTRA2):c.1195G>A (p.Gly399Ser)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_013247.5(HTRA2):c.1195G>A (p.Gly399Ser)
Variation ID: 4341 Accession: VCV000004341.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p13.1 2: 74532698 (GRCh38) [ NCBI UCSC ] 2: 74759825 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 20, 2024 Aug 1, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_013247.5:c.1195G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_037379.1:p.Gly399Ser missense NM_032603.5:c.*908C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
3 prime UTR NM_001289164.3:c.*908C>T 3 prime UTR NM_001289165.2:c.*908C>T 3 prime UTR NM_001321727.1:c.1146-122G>A intron variant NM_001321728.1:c.1116-122G>A intron variant NM_145074.2:c.921-122G>A intron variant NR_135769.1:n.1837G>A non-coding transcript variant NR_135770.1:n.1265G>A non-coding transcript variant NR_135771.1:n.1249G>A non-coding transcript variant NR_135772.1:n.1269G>A non-coding transcript variant NC_000002.12:g.74532698G>A NC_000002.11:g.74759825G>A NG_012163.1:g.8294G>A NG_033037.1:g.2150C>T NG_033047.1:g.26238C>T O43464:p.Gly399Ser - Protein change
- G399S
- Other names
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- Canonical SPDI
- NC_000002.12:74532697:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00359 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00231
Trans-Omics for Precision Medicine (TOPMed) 0.00274
1000 Genomes Project 30x 0.00344
1000 Genomes Project 0.00359
The Genome Aggregation Database (gnomAD), exomes 0.00400
Exome Aggregation Consortium (ExAC) 0.00437
- 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
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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. |
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| HTRA2 | - | - |
GRCh38 GRCh37 |
163 | 299 | |
| LOXL3 | - | - |
GRCh38 GRCh37 |
287 | 497 | |
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. |
|---|---|---|---|---|
| Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Apr 27, 2017 | RCV000004589.12 | |
| Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2024 | RCV000891932.21 |
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. |
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Likely benign
(Aug 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001767502.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 15961413, 18364387, 21701498, 27535533, 26264438, 27884173, 25422467, 25504046)
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Likely benign
(-)
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criteria provided, single submitter
Method: not provided
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005257615.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
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Benign
(Aug 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004155083.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Comment:
HTRA2: BS1, BS2; LOXL3: BS1, BS2
Number of individuals with the variant: 14
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Parkinson disease 13, autosomal dominant, susceptibility to
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000432114.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(-)
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criteria provided, single submitter
Method: research
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Parkinson disease 13, autosomal dominant, susceptibility to
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001435173.1
First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020 |
Comment:
The heterozygous p.Gly399Ser variant in HTRA2 has been identified in 4 individuals with Parkinson disease and individuals without Parkinson disease (PMID: 15961413, 18364387, 25422467), but … (more)
The heterozygous p.Gly399Ser variant in HTRA2 has been identified in 4 individuals with Parkinson disease and individuals without Parkinson disease (PMID: 15961413, 18364387, 25422467), but has also been identified in >1% of South Asian chromosomes and 4 homozoygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for Parkinson disease. (less)
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Benign
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001035780.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024 |
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Uncertain significance
(Jul 01, 2008)
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no assertion criteria provided
Method: literature only
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RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024763.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 14, 2023 |
Comment on evidence:
This variant, formerly titled PARKINSON DISEASE 13, AUTOSOMAL DOMINANT, SUSCEPTIBILITY TO, has been reclassified based on a review of the gnomAD database by Hamosh (2019). … (more)
This variant, formerly titled PARKINSON DISEASE 13, AUTOSOMAL DOMINANT, SUSCEPTIBILITY TO, has been reclassified based on a review of the gnomAD database by Hamosh (2019). In 4 patients with Parkinson disease from a sample of 518 German patients, Strauss et al. (2005) identified a heterozygous 1195G-A transition in exon 7 of the HTRA2 gene, predicting a substitution of serine for glycine at codon 399 (G399S). The mutation was not found among 370 control samples. In transfected cells, the mutation caused mitochondrial dysfunction and altered morphology. By direct sequencing, Simon-Sanchez and Singleton (2008) found a similar frequency of the G399S allele among 644 PD patients (0.77%) and 828 controls (0.72%); the difference was not statistically significant. No association was observed after stratifying by age. Hamosh (2019) noted that the G399S variant was found in 1,069 of 282,850 alleles and in 8 homozygotes in the gnomAD database (December 26, 2019), calling into question the pathogenicity of the variant. (less)
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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. |
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease. | Unal Gulsuner H | Proceedings of the National Academy of Sciences of the United States of America | 2014 | PMID: 25422467 |
| Altered enzymatic activity and allele frequency of OMI/HTRA2 in Alzheimer's disease. | Westerlund M | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2011 | PMID: 21163861 |
| Loss-of-function analysis suggests that Omi/HtrA2 is not an essential component of the PINK1/PARKIN pathway in vivo. | Yun J | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2008 | PMID: 19118185 |
| Genetic variation of Omi/HtrA2 and Parkinson's disease. | Ross OA | Parkinsonism & related disorders | 2008 | PMID: 18790661 |
| Sequencing analysis of OMI/HTRA2 shows previously reported pathogenic mutations in neurologically normal controls. | Simón-Sánchez J | Human molecular genetics | 2008 | PMID: 18364387 |
| Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. | Strauss KM | Human molecular genetics | 2005 | PMID: 15961413 |
| Hamosh, A. Personal Communication. 2019. Baltimore, Md. | - | - | - | - |
Text-mined citations for rs72470545 ...
HelpRecord last updated Oct 20, 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.