ClinVar Genomic variation as it relates to human health
NM_006329.4(FBLN5):c.268G>A (p.Gly90Ser)
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.
Uncertain significance(5); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006329.4(FBLN5):c.268G>A (p.Gly90Ser)
Variation ID: 218359 Accession: VCV000218359.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q32.12 14: 91937058 (GRCh38) [ NCBI UCSC ] 14: 92403402 (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 Apr 15, 2024 Jan 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006329.4:c.268G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006320.2:p.Gly90Ser missense NM_001384158.1:c.391G>A NP_001371087.1:p.Gly131Ser missense NM_001384159.1:c.319G>A NP_001371088.1:p.Gly107Ser missense NM_001384160.1:c.268G>A NP_001371089.1:p.Gly90Ser missense NM_001384161.1:c.100G>A NP_001371090.1:p.Gly34Ser missense NM_001384162.1:c.100G>A NP_001371091.1:p.Gly34Ser missense NC_000014.9:g.91937058C>T NC_000014.8:g.92403402C>T NG_008254.1:g.15645G>A LRG_364:g.15645G>A LRG_364t1:c.268G>A LRG_364p1:p.Gly90Ser Q9UBX5:p.Gly90Ser - Protein change
- G90S, G107S, G131S, G34S
- Other names
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- Canonical SPDI
- NC_000014.9:91937057:C:T
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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.
The Genome Aggregation Database (gnomAD) 0.00019
The Genome Aggregation Database (gnomAD), exomes 0.00038
Trans-Omics for Precision Medicine (TOPMed) 0.00040
Exome Aggregation Consortium (ExAC) 0.00046
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054
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
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 |
544 | 566 |
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 (1) |
criteria provided, single submitter
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Mar 6, 2018 | RCV000202614.7 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Jan 15, 2024 | RCV000521928.28 | |
Benign (1) |
criteria provided, single submitter
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Mar 6, 2018 | RCV001121879.5 | |
not provided (1) |
no classification provided
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- | RCV001249315.2 | |
Pathogenic (1) |
no assertion criteria provided
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Jun 1, 2011 | RCV001843303.2 | |
Uncertain significance (1) |
no assertion criteria provided
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Jan 6, 2016 | RCV003447125.1 |
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
(Mar 06, 2018)
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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: SCV000389483.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Benign
(Mar 06, 2018)
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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: SCV001280534.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Uncertain significance
(Sep 06, 2023)
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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: SCV000617418.4
First in ClinVar: Dec 19, 2017 Last updated: Sep 14, 2023 |
Comment:
Identified in one family in association with features of Charcot-Marie-Tooth or mild neurological and/or connective tissue features; also identified in other unrelated individuals with features … (more)
Identified in one family in association with features of Charcot-Marie-Tooth or mild neurological and/or connective tissue features; also identified in other unrelated individuals with features of Charcot-Marie-Tooth (Auer-Grumbach et al., 2011; Vaeth et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29653220, 23293578, 21576112, 32802946) (less)
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Uncertain significance
(Jun 21, 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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713672.2
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Comment:
BS1, BP4
Number of individuals with the variant: 5
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Uncertain significance
(Jan 15, 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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Invitae
Accession: SCV001198603.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 90 of the FBLN5 protein (p.Gly90Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 90 of the FBLN5 protein (p.Gly90Ser). This variant is present in population databases (rs144288844, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of FBLN5-related conditions (PMID: 21576112, 29653220). ClinVar contains an entry for this variant (Variation ID: 218359). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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
(Sep 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: SCV001961462.14
First in ClinVar: Oct 08, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jun 01, 2011)
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no assertion criteria provided
Method: literature only
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CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1H
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000257548.3
First in ClinVar: Dec 24, 2015 Last updated: Mar 05, 2022 |
Comment on evidence:
In 5 affected members of a family (family C) with demyelinating Charcot-Marie-Tooth disease, type 1H (CMT1H; 619764), Auer-Grumbach et al. (2011) identified a heterozygous c.268G-A … (more)
In 5 affected members of a family (family C) with demyelinating Charcot-Marie-Tooth disease, type 1H (CMT1H; 619764), Auer-Grumbach et al. (2011) identified a heterozygous c.268G-A transition (c.268G-A, NM_006329.3) in exon 4 of the FBLN5 gene, resulting in a gly90-to-ser (G90S) substitution. The variant was not found in the 1000 Genomes Project database, in 517 control individuals, or in previous studies of 1,204 patients with ARMD or 766 control individuals. Two patients, 1 severely affected and 1 clinically asymptomatic, also carried a heterozygous A339T variant in the YARS gene (603623), but this variant did not segregate with the peripheral neuropathy in this family. Three affected family members had hyperelastic skin and 1 had ARMD. Functional studies of the variant were not performed. Skin biopsies from 2 patients with hyperelastic skin showed a marked increase in FBLN5 immunoreactivity, which was present as short plump fibers. An unrelated individual with sporadic occurrence of the disorder was also found to carry the G90S mutation. (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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Hereditary sensorimotor neuropathy with hyperelastic skin
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004174392.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Cutis laxa, autosomal recessive, type 1A
Cutis laxa, autosomal dominant 2
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV001423279.1
First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 |
Comment:
Variant interpretted as Uncertain significance and reported on 10-29-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the … (more)
Variant interpretted as Uncertain significance and reported on 10-29-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Tinnitus (present) , Hyperextensible skin (present) , Joint hypermobility (present) , Feeding difficulties (present) , Abnormality of the intestine (present)
Indication for testing: Not Provided
Age: 40-49 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2018-10-29
Testing laboratory interpretation: Uncertain significance
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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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Fibulin-5 mutation featuring Charcot-Marie-Tooth disease, joint hyperlaxity, and scoliosis. | Kazamel M | Neurology. Genetics | 2020 | PMID: 32802946 |
Genetic analysis of Charcot-Marie-Tooth disease in Denmark and the implementation of a next generation sequencing platform. | Vaeth S | European journal of medical genetics | 2019 | PMID: 29653220 |
Fibulin-5 mutations link inherited neuropathies, age-related macular degeneration and hyperelastic skin. | Auer-Grumbach M | Brain : a journal of neurology | 2011 | PMID: 21576112 |
Text-mined citations for rs144288844 ...
HelpRecord last updated Apr 15, 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.