ClinVar Miner

Submissions for variant NM_213607.3(CCDC103):c.461A>C (p.His154Pro) (rs145457535)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226016 SCV000291913 pathogenic Primary ciliary dyskinesia 2020-09-15 criteria provided, single submitter clinical testing This sequence change replaces histidine with proline at codon 154 of the CCDC103 protein (p.His154Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline. This variant is present in population databases (rs145457535, ExAC 0.3%). This variant has been reported to segregate with primary ciliary dyskinesia in several families of different ethnicities (PMID: 22581229, 26123568, 24357714, 23891469). Most affected individuals that have been reported are homozygous for this variant. ClinVar contains an entry for this variant (Variation ID: 31698). Experimental studies have suggested that this missense change reduces protein function in a zebrafish model system (PMID: 22581229). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723879 SCV000331579 pathogenic not provided 2015-12-29 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000024376 SCV000803497 likely pathogenic Ciliary dyskinesia, primary, 17 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Ciliary dyskinesia, primary, 17, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2-Supporting => Present in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium with allele frequency compatible with recessive disease and high disease prevalence (1:2265 individuals in South Asia populations) (PMID:28790179). PS3 => Well-established functional studies show a deleterious effect (PMID:28790179) (PMID:22581229). PP1-Moderate => PP1 upgraded in strength to Moderate (PMID:26123568,24357714,22581229).
Baylor Genetics RCV000024376 SCV000807600 pathogenic Ciliary dyskinesia, primary, 17 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found once in our laboratory in a homozygous state in an 8-month-old male with CHD (TAPVR, DORV, malposed great vessels), heterotaxy. Heterozygotes are expected to be asymptomatic carriers.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000024376 SCV000845518 uncertain significance Ciliary dyskinesia, primary, 17 2018-08-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000024376 SCV000894130 pathogenic Ciliary dyskinesia, primary, 17 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000024376 SCV000914770 pathogenic Ciliary dyskinesia, primary, 17 2018-11-12 criteria provided, single submitter clinical testing The CCDC103 c.461A>C (p.His154Pro) variant has been identified in four studies in a total of ten probands with primary ciliary dyskinesia, including nine in a homozygous state and one in a compound heterozygous state (Panizzi et al. 2012; D'Andrea et al 2013; Casey et al 2015; Boaretto et al. 2016). The p.His154Pro variant was also found in a heterozygous state in 13 unaffected family members. The p.His154Pro variant was absent from 180 controls and is reported at a frequency of 0.00333 in the South Asian population of the Exome Aggregation Consortium. In vivo functional studies in zebrafish demonstrated that the p.His154Pro variant mRNA could not rescue a mutant phenotype, while the wild type CCDC103 mRNA was able to rescue the mutant phenotype, demonstrating a lack of function of the p.His154Pro variant protein (Panizzi et al. 2012). Based on the evidence, the p.His154Pro variant is classified as pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000226016 SCV000967657 pathogenic Primary ciliary dyskinesia 2018-04-12 criteria provided, single submitter clinical testing The p.His154Pro variant in CCDC103 has been reported in 25 homozygous and 1 comp ound heterozygous individuals with Primary ciliary dyskinesia and segregated in 7 affected family members (Panizzi 2012, D'Andrea 2013, Casey 2015, Boaretto 201 6, Shoemark 2017). All of these individuals were homozygous or compound heterozy gous. This variant has also been reported in ClinVar (Variation ID: 31698). This variant has been identified in 0.32% (97/30782) of South Asian chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs145457535). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Co mputational prediction tools and conservation analyses do not provide strong sup port for or against an impact to the protein. Functional studies provide some ev idence that the p.His154Pro variant may reduce protein function (Panizzi 2012). However, these types of assays may not accurately represent biological function. In summary, the p.His154Pro variant in CCDC103 meets criteria to be classified as pathogenic for Primary ciliary dyskinesia in an autosomal recessive manner ba sed upon segregation studies, presence in affecteds, and functional evidence. AC MG/AMP Criteria applied: PS4, PP1_Strong; PS3_Moderate.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000723879 SCV001250434 pathogenic not provided 2019-11-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000024376 SCV001366352 likely pathogenic Ciliary dyskinesia, primary, 17 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PP4,PP5. This variant was detected in homozygous state.
OMIM RCV000024376 SCV000045669 pathogenic Ciliary dyskinesia, primary, 17 2012-05-13 no assertion criteria provided literature only
GeneReviews RCV000190916 SCV000245802 pathogenic Kartagener syndrome 2015-09-03 no assertion criteria provided literature only
MAGI's Lab - Research,MAGI Group RCV001327943 SCV001432721 uncertain significance Infertility no assertion criteria provided provider interpretation

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