NM_017946.4(FKBP14):c.362dup (p.Glu122fs) AND Ehlers-Danlos syndrome, kyphoscoliotic type, 2

Germline classification:: Pathogenic/Likely pathogenic (13 submissions)
Last evaluated:: Jan 27, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000533832.29

Allele description [Variation Report for NM_017946.4(FKBP14):c.362dup (p.Glu122fs)]

NM_017946.4(FKBP14):c.362dup (p.Glu122fs)

Genes:

FKBP14:FKBP prolyl isomerase 14 [Gene - OMIM - HGNC]
FKBP14-AS1:FKBP14 antisense RNA 1 [Gene - HGNC]

Variant type:

Duplication

Cytogenetic location:

7p14.3

Genomic location:

Preferred name:

NM_017946.4(FKBP14):c.362dup (p.Glu122fs)

Other names:

p.Glu122fs

HGVS:

NC_000007.14:g.30019115dup
NG_032173.1:g.12691dup
NM_017946.4:c.362dupMANE SELECT
NP_060416.1:p.Glu122fs
LRG_454t1:c.362dup
LRG_454:g.12691dup
NC_000007.13:g.30058726_30058727insG
NC_000007.13:g.30058731dup
NM_017946.2:c.362dupC
NM_017946.3:c.362dupC
NR_046478.2:n.648dup
NR_046479.2:n.404dup
p.Glu122Argfs*7

Protein change:

E122fs

Links:

OMIM: 614505.0001; dbSNP: rs542489955

NCBI 1000 Genomes Browser:

rs542489955

Molecular consequence:

NM_017946.4:c.362dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_046478.2:n.648dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_046479.2:n.404dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Ehlers-Danlos syndrome, kyphoscoliotic type, 2
Synonyms:: Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss; Ehlers-Danlos syndrome, kyphoscoliotic and deafness type
Identifiers:: MONDO: MONDO:0013800; MedGen: C3281160; Orphanet: 300179; OMIM: 614557

Recent activity

Clear Turn Off Turn On

Ellobius tRNA-Phe (trnF), 12S ribosomal RNA (rrnS), tRNA-Val (trnV), 16S ribosom...
Ellobius tRNA-Phe (trnF), 12S ribosomal RNA (rrnS), tRNA-Val (trnV), 16S ribosomal RNA (rrnL), and tRNA-Leu (trnL2) genes, complete sequence; NADH dehydrogenase subunit 1 (ND1) gene, complete cds; tRNA-Ile (trnI), tRNA-Gln (trnQ), and tRNA-Met (trnM) genes, complete sequence; NADH dehydrogenase subunit 2 (ND2) gene, complete cds; tRNA-Trp (trnW), tRNA-Ala (trnA), tRNA-Asn (trnN), tRNA-Cys (trnC), and tRNA-Tyr (trnY) genes, complete sequence; cytochrome c oxidase subunit I (COX1) gene, complete cds; tRNA-Ser (trnS2) and tRNA-Asp (trnD) genes, complete sequence; cytochrome c oxidase subunit II (COX2) gene, complete cds; tRNA-Lys (trnK) gene, complete sequence; ATP synthase F0 subunit 8 (ATP8), ATP synthase F0 subunit 6 (ATP6), and cytochrome c oxidase subunit III (COX3) genes, complete cds; tRNA-Gly (trnG) gene, complete sequence; NADH dehydrogenase subunit 3 (ND3) gene, complete cds; tRNA-Arg (trnR) gene, complete sequence; NADH dehydrogenase subunit 4L (ND4L) and NADH dehydrogenase subunit 4 (ND4) genes, complete cds; tRNA-His (trnH), tRNA-Ser (trnS1), and tRNA-Leu (trnL1) genes, complete sequence; NADH dehydrogenase subunit 5 (ND5) and NADH dehydrogenase subunit 6 (ND6) genes, complete cds; tRNA-Glu (trnE) gene, complete sequence; cytochrome b (CYTB) gene, partial cds; and tRNA-Thr (trnT) and tRNA-Pro (trnP) genes and D-loop, complete sequence; mitochondrial.
PopSet: 1929135835

PopSet
Ellobius lutescens sequence.
Ellobius lutescens sequence.
PopSet: 1046760702

PopSet
MHC class II antigen beta chain, partial [Peromyscus maniculatus]
MHC class II antigen beta chain, partial [Peromyscus maniculatus]
gi|15429024|gb|AAK98049.1|

Protein

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000045487	OMIM	no assertion criteria provided	Pathogenic (Feb 10, 2012)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 22265013, 27149304, 30561154
SCV000652309	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 27, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22265013, 24677762, 27149304, 28492532
SCV000929975	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 22265013, 28617417, 24677762, 31132235
SCV001369762	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 20, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001429022	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 10, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001524457	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 26, 2019)	paternal	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22265013, 27905128, 28617417, 24677762, 25741868
SCV001593267	Research Centre for Medical Genetics, Federal State Budgetary Scientific Institution	no assertion criteria provided	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22265013, 28617417
SCV002043791	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	biparental	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31132235, 25741868
SCV002810392	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 22, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003822048	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 30, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003924401	Molecular Genetic Pathology Unit, University Of Rochester Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 16, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22265013, 30561154, 27149304, 28617417, 25741868
SCV004099663	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 8, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV005199982	Solve-RD Consortium	no assertion criteria provided	Likely pathogenic (Jun 1, 2022)	inherited	provider interpretation

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	biparental	yes	not provided	1	not provided	not provided	not provided	clinical testing
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	provider interpretation
not provided	paternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Russia	germline	not provided	5	5	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Ehlers-Danlos syndrome related to FKBP14 mutations: detailed cutaneous phenotype.

Bursztejn AC, Baumann M, Lipsker D.

Clin Exp Dermatol. 2017 Jan;42(1):64-67. doi: 10.1111/ced.12983. Epub 2016 Nov 30. Review.

PubMed [citation]

PMID:: 27905128

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000045487.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000652309.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000929975.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001369762.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001429022.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Baylor Genetics, SCV001524457.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Research Centre for Medical Genetics, Federal State Budgetary Scientific Institution, SCV001593267.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Russia	5	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		5	not provided	5	not provided

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV002043791.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	biparental	yes	not provided	Blood	not provided		not provided	not provided	1	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002810392.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003822048.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Genetic Pathology Unit, University Of Rochester Medical Center, SCV003924401.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004099663.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Solve-RD Consortium, SCV005199982.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	not provided

Description

Variant confirmed as disease-causing by referring clinical team

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

Relating variation to medicine