Submissions for variant NM_021939.4(FKBP10):c.831dup (p.Gly278fs)

dbSNP: rs137853883

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514347	SCV000610649	pathogenic	not provided	2017-03-31	criteria provided, single submitter	clinical testing
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000735367	SCV000854525	pathogenic	Short stature; Recurrent fractures; Kyphosis		criteria provided, single submitter	clinical testing
Mendelics	RCV000505676	SCV001140440	pathogenic	Osteogenesis imperfecta type 11	2019-05-28	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814173	SCV001755165	pathogenic	Abnormality of the skeletal system	2021-07-10	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000514347	SCV001832393	pathogenic	not provided	2019-11-30	criteria provided, single submitter	clinical testing
Suma Genomics	RCV000505676	SCV001847712	pathogenic	Osteogenesis imperfecta type 11		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000514347	SCV002023713	pathogenic	not provided	2022-01-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000514347	SCV002038889	pathogenic	not provided	2019-11-13	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); 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: 20362275, 26538303, 27762305, 27717089, 28346524, 29620724, 31001443, 30993005, 27509835, 29499418, 28492130, 31429852, 31589614, 30755392, 32123938)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000514347	SCV002172866	pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly278Argfs*95) in the FKBP10 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FKBP10 are known to be pathogenic (PMID: 22689593, 22949511). This variant is present in population databases (rs781896189, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with autosomal recessive osteogenesis imperfecta (PMID: 20362275, 26538303, 27509835, 27717089, 27762305). ClinVar contains an entry for this variant (Variation ID: 438659). For these reasons, this variant has been classified as Pathogenic.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000514347	SCV002818251	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV003156099	SCV003845262	pathogenic	See cases	2022-12-21	criteria provided, single submitter	clinical testing
3billion	RCV000505676	SCV004013738	pathogenic	Osteogenesis imperfecta type 11		criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.011%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000438659 / PMID: 20362275 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Illumina Laboratory Services, Illumina	RCV000505676	SCV004801520	pathogenic	Osteogenesis imperfecta type 11	2021-04-23	criteria provided, single submitter	clinical testing	The FKBP10 c.831dupC (p.Gly278ArgfsTer95) variant results in a frameshift and is predicted to result in premature termination or absence of the protein. In a selection of the literature, the p.Gly278ArgfsTer95 variant has been reported in a homozygous state in at least five affected individuals from three unrelated families (Alanay et al. 2010; Shaheen et al. 2011; Kelly et al. 2011), in a compound heterozygous state with another frameshift variant in two affected individuals from one family (Schwarze et al. 2011), and in a compound heterozygous state with a missense variant in two unrelated individuals (Vorster et al. 2017). The affected individuals presented with osteogenesis imperfecta with or without a range of additional phenotypes. In addition, in one study of 91 individuals with non-syndromic osteogenesis imperfecta type 3, the p.Gly278ArgfsTer95 variant was found in a homozygous state in 35/91 (38%) affected individuals who shared the same haplotype (Vorster et al. 2017). In studies on mRNA isolated from patient cells, the p.Gly278ArgfsTer95 was shown to affect mRNA stability resulting in no measurable stable mRNA and absence of protein on Western blotting (Schwarze et al. 2013). The p.Gly278ArgfsTer95 variant was absent from at least 210 ethnically matched control alleles and is found at a frequency of 0.000445 in the African American population of the Genome Aggregation Database. Based on the collective evidence and application of the ACMG criteria, the c.831dupC (p.Gly278ArgfsTer95) variant is classified as pathogenic for osteogenesis imperfecta with or without joint contractures.
Dr.Nikuei Genetic Center	RCV000505676	SCV005200336	pathogenic	Osteogenesis imperfecta type 11	2024-07-10	criteria provided, single submitter	clinical testing
OMIM	RCV000003711	SCV000023874	pathogenic	Osteogenesis imperfecta type 12	2011-06-01	no assertion criteria provided	literature only
OMIM	RCV000034358	SCV000058340	pathogenic	Bruck syndrome 1	2011-06-01	no assertion criteria provided	literature only
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000505676	SCV000599812	pathogenic	Osteogenesis imperfecta type 11	2017-04-20	no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000505676	SCV003927864	pathogenic	Osteogenesis imperfecta type 11	2023-04-01	no assertion criteria provided	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000505676	SCV004807954	uncertain significance	Osteogenesis imperfecta type 11	2024-03-29	flagged submission	clinical testing