NM_017946.4:c.362dupC

Variant names:

• chr7-30019110-T-TG
• rs542489955
• NM_017946.4:c.362dupC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_017946.4(FKBP14):​c.362dupC​(p.Glu122ArgfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000702 in 1,574,900 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00072 (0 hom.)
• Consequence: FKBP14 NM_017946.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26 O:1
• Conservation: PhyloP100: 9.60

Genes affected

FKBP14 (HGNC:18625): (FKBP prolyl isomerase 14) The protein encoded by this gene is a member of the FK506-binding protein family of peptidyl-prolyl cis-trans isomerases. The encoded protein is found in the lumen of the endoplasmic reticulum, where it is thought to accelerate protein folding. Defects in this gene are a cause of a type of Ehlers-Danlos syndrome (EDS). Both a protein-coding variant and noncoding variants are transcribed from this gene. [provided by RefSeq, Mar 2012]

FKBP14-AS1 (HGNC:40990): (FKBP14 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.431 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-30019110-T-TG is Pathogenic according to our data. Variant chr7-30019110-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FKBP14	NM_017946.4	c.362dupC	p.Glu122ArgfsTer7	frameshift_variant	Exon 3 of 4	ENST00000222803.10	NP_060416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FKBP14	ENST00000222803.10	c.362dupC	p.Glu122ArgfsTer7	frameshift_variant	Exon 3 of 4	1	NM_017946.4	ENSP00000222803.5

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000553 AC: 115 AN: 207878 Hom.: 0 AF XY: 0.000527 AC XY: 60 AN XY: 113832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000428

Gnomad FIN exome AF: 0.000287

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.000408

GnomAD4 exome AF: 0.000718 AC: 1022 AN: 1422610 Hom.: 0 Cov.: 31 AF XY: 0.000693 AC XY: 490 AN XY: 707318

Gnomad4 AFR exome AF: 0.000197

Gnomad4 AMR exome AF: 0.000506

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000253

Gnomad4 FIN exome AF: 0.000415

Gnomad4 NFE exome AF: 0.000855

Gnomad4 OTH exome AF: 0.000579

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74484

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000666 Hom.: 0

Bravo AF: 0.000487

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, kyphoscoliotic type, 2 Pathogenic:12 Other:1

Oct 23, 2020

Research Centre for Medical Genetics, Federal State Budgetary Scientific Institution

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 16, 2023

Molecular Genetic Pathology Unit, University Of Rochester Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 08, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Mar 26, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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] -

Jan 20, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 30, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:11

Dec 27, 2019

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 11, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

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Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 22, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP4, PM3_strong, PVS1 -

Mar 03, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PM3 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2016

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 20, 2020

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FKBP14: PVS1, PM3, PM2:Supporting -

Hypotonia;C0699743:Congenital muscular dystrophy;C0749379:Thoracolumbar scoliosis;C1578482:Pes valgus;C1844820:Joint hypermobility Pathogenic:1

Feb 10, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Jan 11, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

FKBP14-related disorder Pathogenic:1

Apr 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs542489955; hg19: chr7-30058726;