ClinVar Genomic variation as it relates to human health
NM_006329.4(FBLN5):c.901C>A (p.Leu301Met)
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.901C>A (p.Leu301Met)
Variation ID: 888450 Accession: VCV000888450.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q32.12 14: 91881380 (GRCh38) [ NCBI UCSC ] 14: 92347724 (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 31, 2020 Feb 14, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006329.4:c.901C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006320.2:p.Leu301Met missense NM_001384158.1:c.1024C>A NP_001371087.1:p.Leu342Met missense NM_001384159.1:c.952C>A NP_001371088.1:p.Leu318Met missense NM_001384160.1:c.901C>A NP_001371089.1:p.Leu301Met missense NM_001384161.1:c.733C>A NP_001371090.1:p.Leu245Met missense NM_001384162.1:c.733C>A NP_001371091.1:p.Leu245Met missense NC_000014.9:g.91881380G>T NC_000014.8:g.92347724G>T NG_008254.1:g.71323C>A LRG_364:g.71323C>A LRG_364t1:c.901C>A LRG_364p1:p.Leu301Met - Protein change
- L301M, L245M, L318M, L342M
- Other names
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- Canonical SPDI
- NC_000014.9:91881379:G: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Exome Aggregation Consortium (ExAC) 0.00030
- 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
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
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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
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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Sep 8, 2017 | RCV001121772.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 8, 2017 | RCV001121773.12 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV001562423.18 | |
Uncertain significance (1) |
no assertion criteria provided
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Jan 6, 2016 | RCV003447317.1 |
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
(Sep 08, 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: SCV001280420.1
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
(Sep 08, 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: SCV001280419.1
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
(Jan 22, 2020)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001473070.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The FBLN5 c.901C>A; p.Leu301Met variant (rs377360782) is reported in the literature in a family affected with cutis laxa (Megarbane 2009). However, all affected individuals in … (more)
The FBLN5 c.901C>A; p.Leu301Met variant (rs377360782) is reported in the literature in a family affected with cutis laxa (Megarbane 2009). However, all affected individuals in this family carried a homozygous variant in a different gene, and the FBLN5 p.Leu301Met variant was speculated to only modify the phenotype in some individuals, though this was not unequivocally demonstrated (Megarbane 2009). The p.Leu301Met variant is found in the South Asian population with an overall allele frequency of 0.09% (28/30616 alleles) in the Genome Aggregation Database. The leucine at codon 301 is moderately conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Given the lack of clinical and functional data, the significance of the p.Leu301Met variant is uncertain at this time. References: Megarbane et al. An autosomal-recessive form of cutis laxa is due to homozygous elastin mutations, and the phenotype may be modified by a heterozygous fibulin 5 polymorphism. J Invest Dermatol. 2009 Jul;129(7):1650-5. (less)
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Uncertain significance
(Mar 11, 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: SCV001785183.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
Has been reported in a patient with retinitis pigmentosa who also carried a HK1 pathogenic variant, as well as other variants in the VCAN and … (more)
Has been reported in a patient with retinitis pigmentosa who also carried a HK1 pathogenic variant, as well as other variants in the VCAN and CC2D2A genes (Yuan et al, 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 888450; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28765615, 19194475) (less)
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Uncertain significance
(Jan 29, 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: SCV002277640.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 301 of the FBLN5 protein (p.Leu301Met). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 301 of the FBLN5 protein (p.Leu301Met). This variant is present in population databases (rs377360782, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with FBLN5-related conditions. ClinVar contains an entry for this variant (Variation ID: 888450). 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%. 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
(Jan 06, 2016)
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no assertion criteria provided
Method: literature only
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Cutis laxa, autosomal dominant
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004174401.1
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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The phenotypic variability of HK1-associated retinal dystrophy. | Yuan Z | Scientific reports | 2017 | PMID: 28765615 |
An autosomal-recessive form of cutis laxa is due to homozygous elastin mutations, and the phenotype may be modified by a heterozygous fibulin 5 polymorphism. | Mégarbané H | The Journal of investigative dermatology | 2009 | PMID: 19194475 |
Text-mined citations for rs377360782 ...
HelpRecord last updated May 27, 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.