ClinVar Genomic variation as it relates to human health
NM_002775.5(HTRA1):c.451C>A (p.Gln151Lys)
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_002775.5(HTRA1):c.451C>A (p.Gln151Lys)
Variation ID: 871447 Accession: VCV000871447.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q26.13 10: 122462103 (GRCh38) [ NCBI UCSC ] 10: 124221619 (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 May 12, 2020 Nov 24, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002775.5:c.451C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002766.1:p.Gln151Lys missense NC_000010.11:g.122462103C>A NC_000010.10:g.124221619C>A NG_011554.1:g.5579C>A - Protein change
- Q151K
- Other names
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p.Gln151Lys
- Canonical SPDI
- NC_000010.11:122462102:C: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00017
Trans-Omics for Precision Medicine (TOPMed) 0.00017
Exome Aggregation Consortium (ExAC) 0.00019
The Genome Aggregation Database (gnomAD) 0.00019
- 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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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HTRA1 | - | - |
GRCh38 GRCh37 |
286 | 349 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2024 | RCV001091419.28 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 19, 2018 | RCV001104661.5 | |
HTRA1-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Jun 18, 2024 | RCV004749604.1 |
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
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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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Uncertain significance
(Mar 19, 2018)
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criteria provided, single submitter
Method: clinical testing
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Macular degeneration
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001261539.1
First in ClinVar: May 31, 2020 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Dec 14, 2023)
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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: SCV002155306.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 151 of the HTRA1 protein (p.Gln151Lys). … (more)
This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 151 of the HTRA1 protein (p.Gln151Lys). This variant is present in population databases (rs754645487, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal dominant CADASIL (PMID: 28782182). ClinVar contains an entry for this variant (Variation ID: 871447). 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 HTRA1 protein function with a negative predictive value of 80%. Studies have shown that this missense change alters HTRA1 gene expression (PMID: 32017060). 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)
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Uncertain significance
(May 01, 2021)
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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: SCV001247456.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
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Uncertain significance
(Jan 19, 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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005412251.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
BP4
Number of individuals with the variant: 1
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Uncertain significance
(Jun 18, 2024)
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no assertion criteria provided
Method: clinical testing
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HTRA1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005367359.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The HTRA1 c.451C>A variant is predicted to result in the amino acid substitution p.Gln151Lys. This patient is heterozygous in the HTRA1 gene for a variant … (more)
The HTRA1 c.451C>A variant is predicted to result in the amino acid substitution p.Gln151Lys. This patient is heterozygous in the HTRA1 gene for a variant designated c.451C>A, which is predicted to result in the amino acid substitution p.Gln151Lys. This variant has been reported in the heterozygous state in a patient with familial cerebral small vessel disease; however, pathogenicity was not established with segregation or functional analysis (Di Donato et al 2017. PubMed ID: 28782182; Pati et al. 2018. PubMed ID: 29546604). This variant was also reported in a thesis in a 68 year old female with a stroke, but no family history of stroke and no white matter hyperintensities or microbleeds on MRI (https://www.repository.cam.ac.uk/bitstream/handle/1810/283203/Final_hardbound_2018-09-24.pdf?sequence=1&isAllowed=y). In this study, the c.451C>A variant was found in 8 control individuals of unknown age and varying disease phenotypes from the BRIDGE study. This variant is reported in 0.036% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (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
HelpTitle | Author | Journal | Year | Link |
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Clinical features and pathogenicity assessment in patients with HTRA1-autosomal dominant disease. | He Z | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2023 | PMID: 36253578 |
Report of two pedigrees with heterozygous HTRA1 variants-related cerebral small vessel disease and literature review. | Zhou H | Molecular genetics & genomic medicine | 2022 | PMID: 35946346 |
Whole-exome sequencing reveals a role of HTRA1 and EGFL8 in brain white matter hyperintensities. | Malik R | Brain : a journal of neurology | 2021 | PMID: 34626176 |
Autosomal Dominant Cerebral Small Vessel Disease in HTRA1 Gene Mutation. | Mahale RR | Annals of Indian Academy of Neurology | 2021 | PMID: 34220097 |
HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature. | Uemura M | Frontiers in neurology | 2020 | PMID: 32719647 |
HTRA1 expression profile and activity on TGF-β signaling in HTRA1 mutation carriers. | Fasano A | Journal of cellular physiology | 2020 | PMID: 32017060 |
A new case of autosomal dominant small vessel disease carrying a novel heterozygous mutation in HTRA1 gene: 2-year follow-up. | Pati AR | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2018 | PMID: 29546604 |
Heterozygous mutations of HTRA1 gene in patients with familial cerebral small vessel disease. | Di Donato I | CNS neuroscience & therapeutics | 2017 | PMID: 28782182 |
Text-mined citations for rs754645487 ...
HelpRecord last updated Nov 30, 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.