The p.Arg373Cys variant (rs864309526) has been reported to segregate with adult onset Charcot-Marie-Tooth neuropathy in three unrelated families and has been identified in an individual who was part of a peripheral neuropathy cohort (Auer-Grumbach 2011, Cheng 2017, Laššuthová 2016, and Šafka Brozková 2013). The p.Arg373Cys is also absent from general population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD) browser. The arginine at codon 373 is highly conserved considering 11 species up to frog (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the FBLN5 protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). Based on the available evidence, the p.Arg373Cys variant is classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_006329.4(FBLN5):c.1117C>T (p.Arg373Cys)
Germline
Classification
Help
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.
(7)
Help
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.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006329.4(FBLN5):c.1117C>T (p.Arg373Cys)
Variation ID: 218358 Accession: VCV000218358.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q32.12 14: 91877555 (GRCh38) [ NCBI UCSC ] 14: 92343899 (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 Sep 16, 2024 Apr 23, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006329.4:c.1117C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006320.2:p.Arg373Cys missense NM_001384158.1:c.1240C>T NP_001371087.1:p.Arg414Cys missense NM_001384159.1:c.1168C>T NP_001371088.1:p.Arg390Cys missense NM_001384160.1:c.1117C>T NP_001371089.1:p.Arg373Cys missense NM_001384161.1:c.949C>T NP_001371090.1:p.Arg317Cys missense NM_001384162.1:c.949C>T NP_001371091.1:p.Arg317Cys missense NC_000014.9:g.91877555G>A NC_000014.8:g.92343899G>A NG_008254.1:g.75148C>T LRG_364:g.75148C>T LRG_364t1:c.1117C>T LRG_364p1:p.Arg373Cys Q9UBX5:p.Arg373Cys - Protein change
- R373C, R317C, R390C, R414C
- Other names
- -
- Canonical SPDI
- NC_000014.9:91877554: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.
- -
- 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
Help
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. |
|||
| FBLN5 | - | - |
GRCh38 GRCh37 |
553 | 576 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 23, 2023 | RCV000756132.25 | |
| Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 23, 2024 | RCV001843302.10 | |
| Uncertain significance (1) |
no assertion criteria provided
|
Jan 6, 2016 | RCV003447124.1 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Nov 09, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000883852.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Comment:
The p.Arg373Cys variant (rs864309526) has been reported to segregate with adult onset Charcot-Marie-Tooth neuropathy in three unrelated families and has been identified in an individual … (more)
The p.Arg373Cys variant (rs864309526) has been reported to segregate with adult onset Charcot-Marie-Tooth neuropathy in three unrelated families and has been identified in an individual who was part of a peripheral neuropathy cohort (Auer-Grumbach 2011, Cheng 2017, Laššuthová 2016, and Šafka Brozková 2013). The p.Arg373Cys is also absent from general population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD) browser. The arginine at codon 373 is highly conserved considering 11 species up to frog (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the FBLN5 protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). Based on the available evidence, the p.Arg373Cys variant is classified as likely pathogenic. (less)
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Likely pathogenic
(Oct 23, 2018)
|
criteria provided, single submitter
Method: research
|
Charcot-Marie-Tooth disease, demyelinating, IIA 1H
Affected status: yes
Allele origin:
paternal
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI-WGS-HudsonAlpha
Accession: SCV000886431.2 First in ClinVar: Mar 08, 2017 Last updated: May 20, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Pes cavus (present)
|
|
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Pathogenic
(Sep 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002245453.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the FBLN5 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the FBLN5 protein (p.Arg373Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant FBLN5-related conditions (PMID: 21576112, 23328402, 28332470, 31945625). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218358). 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. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Apr 23, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease, demyelinating, IIA 1H
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV005013290.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
|
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Likely pathogenic
(Oct 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001788378.2
First in ClinVar: Aug 21, 2021 Last updated: Sep 16, 2024 |
Comment:
Segregates with disease in many affected individuals with neuropathies from several families tested at GeneDx and reported in the published literature (PMID: 21576112, 23328402, 28332470, … (more)
Segregates with disease in many affected individuals with neuropathies from several families tested at GeneDx and reported in the published literature (PMID: 21576112, 23328402, 28332470, 32802946, 31945625); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29412171, 23328402, 27549087, 23293578, 24244300, 21576112, 32802946, 31945625, 31589614, 32757322, 28332470) (less)
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Pathogenic
(Jul 01, 2013)
|
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
|
OMIM
Accession: SCV000257547.3
First in ClinVar: Dec 24, 2015 Last updated: Mar 05, 2022 |
Comment on evidence:
In affected members of a large Austrian kindred (families A and B) with demyelinating Charcot-Marie-Tooth disease, type 1H (CMT1H; 619764), Auer-Grumbach et al. (2011), identified … (more)
In affected members of a large Austrian kindred (families A and B) with demyelinating Charcot-Marie-Tooth disease, type 1H (CMT1H; 619764), Auer-Grumbach et al. (2011), identified a heterozygous c.1117C-T transition (c.1117C-T, NM_006329.3) in exon 10 of the FBLN5 gene, resulting in an arg373-to-cys (R373C) substitution at a highly conserved residue in the fibulin-type C terminus. The mutation, which was found by analysis of protein coding genes within a region identified through linkage analysis, segregated with the disorder in the family and was not found in 317 control individuals or in the 1000 Genomes Project database. Functional studies of the variant were not performed. Nerve and muscle biopsy of 1 patient (B5) showed no obvious changes in the immunohistochemical staining patterns of FBLN5 and elastin, but skin biopsy from another patient (B9) showed mild changes in the structure and arrangement of FBLN5 and elastin; neither of these patients had clinical skin abnormalities or ARMD. Safka Brozkova et al. (2013) identified a heterozygous R373C mutation in affected members of a Czech family with CMT1H. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP (build 132) or Exome Variant Server databases. Functional studies of the variant were not performed. Haplotype analysis indicated that the mutation occurred independently from that in the family reported by Auer-Grumbach et al. (2011). None of the Czech patients had ARMD. In 3 affected members spanning 3 generations of a Chinese family with CMT1H, Cheng et al. (2017) identified a heterozygous R373C mutation in the FBLN5 gene. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, with evidence of variable expressivity and age-dependent penetrance. Functional studies of the variant were not performed. Safka Brozkova et al. (2020) identified a heterozygous R373C mutation in the FBLN5 gene in affected members of 15 unrelated families from Austria, the Czech Republic, and France with CMT1H. The mutation, which was found by exome sequencing and segregated with the disorder in the families, was not present in the gnomAD database. Haplotype analysis indicated that some of the Czech families shared a similar haplotype, although others had independent mutational events. Functional studies of the variant were not performed. Three of the families had previously been reported. (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
|
Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004174393.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the FBLN5 protein (p.Arg373Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant FBLN5-related conditions (PMID: 21576112, 23328402, 28332470, 31945625). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218358). 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. For these reasons, this variant has been classified as Pathogenic.
Comment:
Segregates with disease in many affected individuals with neuropathies from several families tested at GeneDx and reported in the published literature (PMID: 21576112, 23328402, 28332470, 32802946, 31945625); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29412171, 23328402, 27549087, 23293578, 24244300, 21576112, 32802946, 31945625, 31589614, 32757322, 28332470)
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. |
Comment:
The p.Arg373Cys variant (rs864309526) has been reported to segregate with adult onset Charcot-Marie-Tooth neuropathy in three unrelated families and has been identified in an individual who was part of a peripheral neuropathy cohort (Auer-Grumbach 2011, Cheng 2017, Laššuthová 2016, and Šafka Brozková 2013). The p.Arg373Cys is also absent from general population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD) browser. The arginine at codon 373 is highly conserved considering 11 species up to frog (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the FBLN5 protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). Based on the available evidence, the p.Arg373Cys variant is classified as likely pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the FBLN5 protein (p.Arg373Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant FBLN5-related conditions (PMID: 21576112, 23328402, 28332470, 31945625). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218358). 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. For these reasons, this variant has been classified as Pathogenic.
Comment:
Segregates with disease in many affected individuals with neuropathies from several families tested at GeneDx and reported in the published literature (PMID: 21576112, 23328402, 28332470, 32802946, 31945625); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29412171, 23328402, 27549087, 23293578, 24244300, 21576112, 32802946, 31945625, 31589614, 32757322, 28332470)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Demyelinating Charcot-Marie-Tooth neuropathy associated with FBLN5 mutations. | Safka Brozkova D | European journal of neurology | 2020 | PMID: 32757322 |
| Charcot-Marie-Tooth disease with a mutation in FBLN5 accompanying with the small vasculitis and widespread onion-bulb formations. | Yamagishi Y | Journal of the neurological sciences | 2020 | PMID: 31945625 |
| Adult-onset demyelinating neuropathy associated with FBLN5 gene mutation. | Cheng S | Clinical neuropathology | 2017 | PMID: 28332470 |
| Czech family confirms the link between FBLN5 and Charcot-Marie-Tooth type 1 neuropathy. | Šafka Brozková D | Brain : a journal of neurology | 2013 | PMID: 23328402 |
| 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 rs864309526 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.