This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2. This variant was detected in homozygous state.
ClinVar Genomic variation as it relates to human health
NM_017946.4(FKBP14):c.362dup (p.Glu122fs)
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.
(27)
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
27
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_017946.4(FKBP14):c.362dup (p.Glu122fs)
Variation ID: 279809 Accession: VCV000279809.67
- Type and length
-
Duplication, 1 bp
- Location
-
Cytogenetic: 7p14.3 7: 30019110-30019111 (GRCh38) [ NCBI UCSC ] 7: 30058726-30058727 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 26, 2024 Jan 27, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_017946.4:c.362dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060416.1:p.Glu122fs frameshift NM_017946.3:c.362dupC NR_046478.2:n.648dup non-coding transcript variant NR_046479.2:n.404dup non-coding transcript variant NC_000007.14:g.30019115dup NC_000007.13:g.30058731dup NG_032173.1:g.12691dup LRG_454:g.12691dup LRG_454t1:c.362dup - Protein change
- E122fs
- Other names
-
p.Glu122fs
- Canonical SPDI
- NC_000007.14:30019110:GGGGG:GGGGGG
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00100 (GGGGGG)
-
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. |
|||
| FKBP14 | - | - |
GRCh38 GRCh37 |
3 | 247 | |
| FKBP14-AS1 | - | - | - | GRCh38 | - | 220 |
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 (11) |
criteria provided, multiple submitters, no conflicts
|
Apr 1, 2023 | RCV000262568.45 | |
| Pathogenic (1) |
no assertion criteria provided
|
Feb 10, 2016 | RCV000415176.3 | |
| Pathogenic/Likely pathogenic (13) |
criteria provided, multiple submitters, no conflicts
|
Jan 27, 2024 | RCV000533832.29 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 11, 2023 | RCV002460064.4 | |
|
FKBP14-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Apr 18, 2024 | RCV004757185.1 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jan 09, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000705359.2
First in ClinVar: Dec 06, 2016 Last updated: Jun 02, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Jul 10, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Ehlers-Danlos syndrome, kyphoscoliotic type, 2
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429022.1
First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001448093.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Hyperextensible skin (present) , Joint hypermobility (present) , Kyphoscoliosis (present) , Scoliosis (present)
Sex: female
|
|
|
Likely pathogenic
(Jan 20, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Ehlers-Danlos syndrome, kyphoscoliotic type, 2
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369762.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2. This variant was detected in homozygous state.
|
|
|
Pathogenic
(Apr 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329349.9
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24677762, 22265013, 33879512, 27149304, 27905128, 30561154, 31063316, 31132235, 31980526, 31589614, 33587123, 34426522, 34504686, 26582918, 28617417, 27535533) (less)
|
|
|
Pathogenic
(Jan 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Ehlers-Danlos syndrome, kyphoscoliotic type, 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000652309.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu122Argfs*7) in the FKBP14 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Glu122Argfs*7) in the FKBP14 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FKBP14 are known to be pathogenic (PMID: 22265013). This variant is present in population databases (rs542489955, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with Ehlers-Danlos syndrome (PMID: 22265013, 24677762, 27149304). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 279809). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Ehlers-Danlos syndrome, kyphoscoliotic type, 2
Affected status: yes
Allele origin:
paternal
|
Baylor Genetics
Accession: SCV001524457.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in multiple affected families as disease-causing … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in multiple affected families as disease-causing [PMID 22265013, 27905128, 28617417, 24677762] (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Ehlers-Danlos syndrome, kyphoscoliotic type, 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
biparental
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV002043791.1
First in ClinVar: Dec 29, 2021 Last updated: Dec 29, 2021 |
Sex: female
Tissue: Blood
Secondary finding: no
|
|
|
Pathogenic
(Mar 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002051615.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 11, 2022 |
Comment:
PVS1, PM2, PM3
|
|
|
Pathogenic
(Jul 20, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501019.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
|
Pathogenic
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Ehlers-Danlos syndrome, kyphoscoliotic type, 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002810392.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Dec 27, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV002817277.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with … (more)
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with this gene (PMID: 30561154, 22265013, 28617417, 27905128).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. (less)
|
|
|
Pathogenic
(May 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Ehlers-Danlos syndrome, kyphoscoliotic type, 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Molecular Genetic Pathology Unit, University Of Rochester Medical Center
Accession: SCV003924401.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
This variant was identified in the homozygous state in a patient with kyphoscoliotic Ehlers-Danlos Syndrome (kEDS). This frameshift variant causes a premature termination codon and … (more)
This variant was identified in the homozygous state in a patient with kyphoscoliotic Ehlers-Danlos Syndrome (kEDS). This frameshift variant causes a premature termination codon and is predicted to result in loss-of-function. This variant is a known pathogenic variant that has been reported multiple times in patients with kEDS, as either homozygous or compound heterozygous. This variant has been submitted to ClinVar as pathogenic over twenty times. (less)
|
|
|
Pathogenic
(Sep 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Ehlers-Danlos syndrome, kyphoscoliotic type, 2
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004099663.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
Variant summary: FKBP14 c.362dupC (p.Glu122ArgfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: FKBP14 c.362dupC (p.Glu122ArgfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00055 in 207878 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FKBP14 causing Ehlers-Danlos Syndrome, Kyphoscoliotic And Deafness Type. c.362dupC has been reported in the literature in multiple individuals affected with Ehlers-Danlos Syndrome, Kyphoscoliotic And Deafness Type (e.g., Colman_2022). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 36054293). 20 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Oct 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715926.3
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Comment:
PP1, PP4, PM3_strong, PVS1
Number of individuals with the variant: 4
|
|
|
Pathogenic
(Apr 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Ehlers-Danlos syndrome, kyphoscoliotic type, 2
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003822048.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002618108.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.362dupC pathogenic mutation, located in coding exon 3 of the FKBP14 gene, results from a duplication of C at nucleotide position 362, causing a … (more)
The c.362dupC pathogenic mutation, located in coding exon 3 of the FKBP14 gene, results from a duplication of C at nucleotide position 362, causing a translational frameshift with a predicted alternate stop codon (p.E122Rfs*7). This mutation has been reported in multiple individuals with autosomal recessive Ehlers-Danlos syndrome, kyphoscoliotic type 2 (kEDS), including homozygous and compound heterozygous cases (Baumann M et al. Am. J. Hum. Genet., 2012 Feb;90:201-16;Murray ML et al. Am. J. Med. Genet. A, 2014 Jul;164A:1750-5; Dordoni C et al. Am. J. Med. Genet. A, 2016 08;170:2031-8; Bursztejn AC et al. Clin. Exp. Dermatol., 2017 Jan;42:64-67;Giunta C et al. Genet. Med., 2018 01;20:42-54). Fibroblast and mRNA studies from affected individuals showed absent and significantly reduced expression, respectively (Baumann M et al. Am. J. Hum. Genet., 2012 Feb;90:201-16). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Apr 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001747506.20
First in ClinVar: Jul 10, 2021 Last updated: Oct 20, 2024 |
Comment:
FKBP14: PVS1, PM3, PM2:Supporting
Number of individuals with the variant: 8
|
|
|
Pathogenic
(Feb 10, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Congenital muscular dystrophy
Joint hypermobility Hypotonia Thoracolumbar scoliosis Pes valgus
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492576.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
|
|
|
Pathogenic
(Jun 01, 2016)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV000778202.1
First in ClinVar: Jun 02, 2018 Last updated: Jun 02, 2018 |
|
|
|
Pathogenic
(Feb 10, 2012)
|
no assertion criteria provided
Method: literature only
|
EHLERS-DANLOS SYNDROME, KYPHOSCOLIOTIC TYPE, 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000045487.4
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
In 5 patients with Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss (EDSKSCL2; 614557) from 4 unrelated families of Austrian, Italian, French, and Turkish … (more)
In 5 patients with Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss (EDSKSCL2; 614557) from 4 unrelated families of Austrian, Italian, French, and Turkish origin, Baumann et al. (2012) identified homozygosity for a 1-bp duplication within a 5C-nucleotide repeat in exon 3 (c.362dupC, NM_017946.2) of the FKBP14 gene, causing a frameshift predicted to result in a premature termination codon (Glu122ArgfsTer7). Western blot analysis demonstrated absence of FKBP14 in patient fibroblasts, and qRT-PCR analysis showed strongly reduced FKBP14 expression compared to controls, consistent with nonsense-mediated decay. In an unrelated patient with EDSKMH, Baumann et al. (2012) identified compound heterozygosity for the 362dupC mutation and a 19-bp deletion (42_60del) in exon 1 of the FKBP14 gene (614505.0002), also predicted to result in a premature termination codon. The 362dupC mutation was linked to the same haplotype in all individuals, despite their geographically diverse origins, suggesting a possible founder event. Neither mutation was found in 200 controls of European descent. In an 8-year-old Italian boy with EDSKSCL, Dordoni et al. (2016) identified compound heterozygosity for the recurrent c.362dupC mutation in exon 3 of the FKBP14 gene, and an in-frame 3-bp deletion (c.573_575del; 614505.0004) in exon 4, causing deletion of 1 residue (Glu191del). His unaffected parents were each heterozygous for 1 of the mutations. By sequencing of genes in a targeted panel for Ehlers-Danlos syndrome, Castori et al. (2019) identified homozygosity for the recurrent c.362dupC mutation in the FKBP14 gene in a 15-year-old girl with EDSKSCL who showed severe involvement of the lower limb muscles. Her unaffected parents were heterozygous for the mutation. (less)
|
|
|
Pathogenic
(Oct 23, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Ehlers-Danlos syndrome, kyphoscoliotic type, 2
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Research Centre for Medical Genetics, Federal State Budgetary Scientific Institution
Accession: SCV001593267.1
First in ClinVar: May 16, 2021 Last updated: May 16, 2021 |
Number of individuals with the variant: 5
Age: 0-9 years
Sex: mixed
Ethnicity/Population group: Russia
Geographic origin: Russia
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808321.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001964783.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Likely pathogenic
(Jun 01, 2022)
|
no assertion criteria provided
Method: provider interpretation
|
Ehlers-Danlos syndrome, kyphoscoliotic type, 2
Affected status: yes
Allele origin:
inherited
|
Solve-RD Consortium
Accession: SCV005199982.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024
Comment:
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more)
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)
|
Comment:
Variant confirmed as disease-causing by referring clinical team
|
|
|
Pathogenic
(Apr 18, 2024)
|
no assertion criteria provided
Method: clinical testing
|
FKBP14-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005352335.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The FKBP14 c.362dupC variant is predicted to result in a frameshift and premature protein termination (p.Glu122Argfs*7). This variant has been reported in the homozygous state … (more)
The FKBP14 c.362dupC variant is predicted to result in a frameshift and premature protein termination (p.Glu122Argfs*7). This variant has been reported in the homozygous state within individuals presenting with kyphoscoliotic Ehlers-Danlos syndrome (Giunta et al. 2018. PubMed ID: 28617417; Baumawnn et al. 2012. PubMed ID: 22265013; Bursztejn et al. 2017. PubMed ID: 27905128). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in FKBP14 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Ehlers-Danlos syndrome, kyphoscoliotic type, 2
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000929975.2
First in ClinVar: Jul 31, 2019 Last updated: Oct 01, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24677762, 22265013, 33879512, 27149304, 27905128, 30561154, 31063316, 31132235, 31980526, 31589614, 33587123, 34426522, 34504686, 26582918, 28617417, 27535533)
Comment:
This sequence change creates a premature translational stop signal (p.Glu122Argfs*7) in the FKBP14 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FKBP14 are known to be pathogenic (PMID: 22265013). This variant is present in population databases (rs542489955, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with Ehlers-Danlos syndrome (PMID: 22265013, 24677762, 27149304). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 279809). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in multiple affected families as disease-causing [PMID 22265013, 27905128, 28617417, 24677762]
Comment:
PVS1, PM2, PM3
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with this gene (PMID: 30561154, 22265013, 28617417, 27905128).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Comment:
This variant was identified in the homozygous state in a patient with kyphoscoliotic Ehlers-Danlos Syndrome (kEDS). This frameshift variant causes a premature termination codon and is predicted to result in loss-of-function. This variant is a known pathogenic variant that has been reported multiple times in patients with kEDS, as either homozygous or compound heterozygous. This variant has been submitted to ClinVar as pathogenic over twenty times.
Comment:
Variant summary: FKBP14 c.362dupC (p.Glu122ArgfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00055 in 207878 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FKBP14 causing Ehlers-Danlos Syndrome, Kyphoscoliotic And Deafness Type. c.362dupC has been reported in the literature in multiple individuals affected with Ehlers-Danlos Syndrome, Kyphoscoliotic And Deafness Type (e.g., Colman_2022). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 36054293). 20 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
PP1, PP4, PM3_strong, PVS1
Comment:
The c.362dupC pathogenic mutation, located in coding exon 3 of the FKBP14 gene, results from a duplication of C at nucleotide position 362, causing a translational frameshift with a predicted alternate stop codon (p.E122Rfs*7). This mutation has been reported in multiple individuals with autosomal recessive Ehlers-Danlos syndrome, kyphoscoliotic type 2 (kEDS), including homozygous and compound heterozygous cases (Baumann M et al. Am. J. Hum. Genet., 2012 Feb;90:201-16;Murray ML et al. Am. J. Med. Genet. A, 2014 Jul;164A:1750-5; Dordoni C et al. Am. J. Med. Genet. A, 2016 08;170:2031-8; Bursztejn AC et al. Clin. Exp. Dermatol., 2017 Jan;42:64-67;Giunta C et al. Genet. Med., 2018 01;20:42-54). Fibroblast and mRNA studies from affected individuals showed absent and significantly reduced expression, respectively (Baumann M et al. Am. J. Hum. Genet., 2012 Feb;90:201-16). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
FKBP14: PVS1, PM3, PM2:Supporting
Comment:
Variant confirmed as disease-causing by referring clinical team
Comment:
The FKBP14 c.362dupC variant is predicted to result in a frameshift and premature protein termination (p.Glu122Argfs*7). This variant has been reported in the homozygous state within individuals presenting with kyphoscoliotic Ehlers-Danlos syndrome (Giunta et al. 2018. PubMed ID: 28617417; Baumawnn et al. 2012. PubMed ID: 22265013; Bursztejn et al. 2017. PubMed ID: 27905128). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in FKBP14 are expected to be pathogenic. This variant is interpreted as pathogenic.
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:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2. This variant was detected in homozygous state.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24677762, 22265013, 33879512, 27149304, 27905128, 30561154, 31063316, 31132235, 31980526, 31589614, 33587123, 34426522, 34504686, 26582918, 28617417, 27535533)
Comment:
This sequence change creates a premature translational stop signal (p.Glu122Argfs*7) in the FKBP14 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FKBP14 are known to be pathogenic (PMID: 22265013). This variant is present in population databases (rs542489955, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with Ehlers-Danlos syndrome (PMID: 22265013, 24677762, 27149304). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 279809). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in multiple affected families as disease-causing [PMID 22265013, 27905128, 28617417, 24677762]
Comment:
PVS1, PM2, PM3
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with this gene (PMID: 30561154, 22265013, 28617417, 27905128).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Comment:
This variant was identified in the homozygous state in a patient with kyphoscoliotic Ehlers-Danlos Syndrome (kEDS). This frameshift variant causes a premature termination codon and is predicted to result in loss-of-function. This variant is a known pathogenic variant that has been reported multiple times in patients with kEDS, as either homozygous or compound heterozygous. This variant has been submitted to ClinVar as pathogenic over twenty times.
Comment:
Variant summary: FKBP14 c.362dupC (p.Glu122ArgfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00055 in 207878 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FKBP14 causing Ehlers-Danlos Syndrome, Kyphoscoliotic And Deafness Type. c.362dupC has been reported in the literature in multiple individuals affected with Ehlers-Danlos Syndrome, Kyphoscoliotic And Deafness Type (e.g., Colman_2022). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 36054293). 20 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
PP1, PP4, PM3_strong, PVS1
Comment:
The c.362dupC pathogenic mutation, located in coding exon 3 of the FKBP14 gene, results from a duplication of C at nucleotide position 362, causing a translational frameshift with a predicted alternate stop codon (p.E122Rfs*7). This mutation has been reported in multiple individuals with autosomal recessive Ehlers-Danlos syndrome, kyphoscoliotic type 2 (kEDS), including homozygous and compound heterozygous cases (Baumann M et al. Am. J. Hum. Genet., 2012 Feb;90:201-16;Murray ML et al. Am. J. Med. Genet. A, 2014 Jul;164A:1750-5; Dordoni C et al. Am. J. Med. Genet. A, 2016 08;170:2031-8; Bursztejn AC et al. Clin. Exp. Dermatol., 2017 Jan;42:64-67;Giunta C et al. Genet. Med., 2018 01;20:42-54). Fibroblast and mRNA studies from affected individuals showed absent and significantly reduced expression, respectively (Baumann M et al. Am. J. Hum. Genet., 2012 Feb;90:201-16). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
FKBP14: PVS1, PM3, PM2:Supporting
Comment:
Variant confirmed as disease-causing by referring clinical team
Comment:
The FKBP14 c.362dupC variant is predicted to result in a frameshift and premature protein termination (p.Glu122Argfs*7). This variant has been reported in the homozygous state within individuals presenting with kyphoscoliotic Ehlers-Danlos syndrome (Giunta et al. 2018. PubMed ID: 28617417; Baumawnn et al. 2012. PubMed ID: 22265013; Bursztejn et al. 2017. PubMed ID: 27905128). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in FKBP14 are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Let Time Teach You: A Case Report of a Double Diagnosis of 17P Duplication and Ehlers-Danlos Syndrome. | Castronovo P | Genes | 2022 | PMID: 36553464 |
| Kyphoscoliotic Ehlers-Danlos syndrome caused by pathogenic variants in FKBP14: Further insights into the phenotypic spectrum and pathogenic mechanisms. | Colman M | Human mutation | 2022 | PMID: 36054293 |
| Ehlers-Danlos syndrome kyphoscoliotic type 2 caused by mutations in the FKBP14 gene: an analysis of five cases. | Semyachkina AN | F1000Research | 2021 | PMID: 34504686 |
| Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing: An Interim Report of the Genomic Medicine for Ill Neonates and Infants (GEMINI) Study. | Maron JL | JAMA pediatrics | 2021 | PMID: 33587123 |
| FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome. | Adam MP | - | 2019 | PMID: 31132235 |
| FKBP14 kyphoscoliotic Ehlers-Danlos Syndrome in adolescent patient: the first Colombian report. | Ruiz-Botero F | Archivos argentinos de pediatria | 2019 | PMID: 31063316 |
| Primary muscle involvement in a 15-year-old girl with the recurrent homozygous c.362dupC variant in FKBP14. | Castori M | American journal of medical genetics. Part A | 2019 | PMID: 30561154 |
| A cohort of 17 patients with kyphoscoliotic Ehlers-Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical and mutational spectrum and description of the natural history. | Giunta C | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 28617417 |
| Ehlers-Danlos syndrome related to FKBP14 mutations: detailed cutaneous phenotype. | Bursztejn AC | Clinical and experimental dermatology | 2017 | PMID: 27905128 |
| Further delineation of FKBP14-related Ehlers-Danlos syndrome: A patient with early vascular complications and non-progressive kyphoscoliosis, and literature review. | Dordoni C | American journal of medical genetics. Part A | 2016 | PMID: 27149304 |
| FKBP14-related Ehlers-Danlos syndrome: expansion of the phenotype to include vascular complications. | Murray ML | American journal of medical genetics. Part A | 2014 | PMID: 24677762 |
| Mutations in FKBP14 cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss. | Baumann M | American journal of human genetics | 2012 | PMID: 22265013 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FKBP14 | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs542489955 ...
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 25, 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.