ClinVar Genomic variation as it relates to human health
NM_006329.4(FBLN5):c.1051C>T (p.Arg351Trp)
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_006329.4(FBLN5):c.1051C>T (p.Arg351Trp)
Variation ID: 5481 Accession: VCV000005481.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q32.12 14: 91877621 (GRCh38) [ NCBI UCSC ] 14: 92343965 (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 Mar 8, 2017 Feb 14, 2024 Dec 12, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006329.4:c.1051C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006320.2:p.Arg351Trp missense NM_001384158.1:c.1174C>T NP_001371087.1:p.Arg392Trp missense NM_001384159.1:c.1102C>T NP_001371088.1:p.Arg368Trp missense NM_001384160.1:c.1051C>T NP_001371089.1:p.Arg351Trp missense NM_001384161.1:c.883C>T NP_001371090.1:p.Arg295Trp missense NM_001384162.1:c.883C>T NP_001371091.1:p.Arg295Trp missense NC_000014.9:g.91877621G>A NC_000014.8:g.92343965G>A NG_008254.1:g.75082C>T LRG_364:g.75082C>T LRG_364t1:c.1051C>T LRG_364p1:p.Arg351Trp Q9UBX5:p.Arg351Trp - Protein change
- R351W, R295W, R368W, R392W
- Other names
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- Canonical SPDI
- NC_000014.9:91877620: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00008
The Genome Aggregation Database (gnomAD) 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00015
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
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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FBLN5 | - | - |
GRCh38 GRCh37 |
546 | 568 |
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. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000005815.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001119789.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 12, 2023 | RCV001577844.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 22, 2019 | RCV002251883.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 15, 2021 | RCV002490323.1 | |
Uncertain significance (1) |
no assertion criteria provided
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Jan 6, 2016 | RCV003447073.1 |
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. |
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Macular degeneration, age-related, 3
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001278231.1
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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cutis laxa
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001278232.1
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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Oct 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cutis laxa, autosomal recessive, type 1A
Macular degeneration, age-related, 3 Cutis laxa, autosomal dominant 2 Charcot-Marie-Tooth disease, demyelinating, IIA 1H
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002792778.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Dec 12, 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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Invitae
Accession: SCV002251354.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 351 of the FBLN5 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 351 of the FBLN5 protein (p.Arg351Trp). This variant is present in population databases (rs28939073, gnomAD 0.03%). This missense change has been observed in individual(s) with age-related macular degeneration (PMID: 15269314). ClinVar contains an entry for this variant (Variation ID: 5481). 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 FBLN5 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect FBLN5 function (PMID: 16652333). 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 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Macular degeneration, age-related, 3
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001139500.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Aug 18, 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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GeneDx
Accession: SCV001805315.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Identified in a patient with age-related macular degeneration in the published literature (Stone et al., 2004) Functional data suggests that R351W indicates increased self-association of … (more)
Identified in a patient with age-related macular degeneration in the published literature (Stone et al., 2004) Functional data suggests that R351W indicates increased self-association of the dimers (Jones et al., 2010), though additional studies are need to elucidate the pathogenicity of R351W In silico analysis supports that this missense variant has a deleterious effect on protein structure/function Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 5481; Landrum et al., 2016) This variant is associated with the following publications: (PMID: 20007835, 15269314, 21576112) (less)
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Uncertain significance
(Apr 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523474.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PM2, PP3
Clinical Features:
Abnormal peripheral nervous system morphology (present) , Spinal muscular atrophy (present) , Abnormal muscle physiology (present)
Geographic origin: Brazil
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Pathogenic
(Jul 22, 2004)
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no assertion criteria provided
Method: literature only
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MACULAR DEGENERATION, AGE-RELATED, 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025997.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 05, 2022 |
Comment on evidence:
In a patient with age-related macular degeneration-3 and basal laminar drusen (ARMD3; 608895), Stone et al. (2004) identified a heterozygous c.1051C-T transition in the FBLN5 … (more)
In a patient with age-related macular degeneration-3 and basal laminar drusen (ARMD3; 608895), Stone et al. (2004) identified a heterozygous c.1051C-T transition in the FBLN5 gene, resulting in an arg351-to-trp (R351W) substitution. This patient was 1 of 402 patients with age-related macular degeneration who were examined in a retina clinic. (less)
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Uncertain significance
(Jan 06, 2016)
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no assertion criteria provided
Method: literature only
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None
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004174405.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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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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Structural effects of fibulin 5 missense mutations associated with age-related macular degeneration and cutis laxa. | Jones RP | Investigative ophthalmology & visual science | 2010 | PMID: 20007835 |
Reduced secretion of fibulin 5 in age-related macular degeneration and cutis laxa. | Lotery AJ | Human mutation | 2006 | PMID: 16652333 |
Missense variations in the fibulin 5 gene and age-related macular degeneration. | Stone EM | The New England journal of medicine | 2004 | PMID: 15269314 |
Text-mined citations for rs28939073 ...
HelpRecord last updated Mar 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.