ClinVar Miner

Submissions for variant NM_183374.3(CYP26C1):c.845_851dup (p.Gln284fs)

gnomAD frequency: 0.00212  dbSNP: rs565866662
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000677253 SCV000681430 likely benign Optic nerve hypoplasia criteria provided, single submitter research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000825029 SCV000966226 uncertain significance not specified 2018-11-20 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gln284His fsX129 variant in CYP26C1 has been reported in 3 homozygous and 2 compound heter ozygous individuals with focal facial dermal dysplasia 4 (FFDD 4)and segregated with disease in 1 affected relative (Slavotinek 2013, Lee 2018). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 284 and leads to a premature termination codon 129 amino acids downstream. This termination codon occurs within the terminal 50 bases of the second to last exon and is, therefore, likely to escape nonsense mediated de cay (NMD) and result in a truncated protein. This variant has also been identifi ed in 0.7% (177/25112) of Finnish and 0.3% (392/128808) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is higher than expected cons idering the rarity of FFDD 4. It has been speculated that this is due to incompl ete penetrance or under ascertainment (Slavotinek 2013); however, it is unclear at this time. In summary, while there is some suspicion for a pathogenic role, t he clinical significance of the p.Gln284HisfsX129 variant is uncertain due to co nflicting data. ACMG/AMP Criteria applied: PM3, PM4, BS1_Supporting.
Invitae RCV000968474 SCV001115932 likely benign not provided 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000968474 SCV003935703 likely pathogenic not provided 2023-06-20 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect with this variant demonstrating 4% of enzyme activity as compared to wild-type (Slavotinek et al., 2013); Frameshift variant predicted to result in protein truncation as the last 239 amino acids are replaced with 128 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 23161670, 32040484, 34426522, 29263414)
CeGaT Center for Human Genetics Tuebingen RCV000968474 SCV004698409 pathogenic not provided 2024-03-01 criteria provided, single submitter clinical testing CYP26C1: PVS1, PM2, PM3, PP4
OMIM RCV002285162 SCV000056850 pathogenic Focal facial dermal dysplasia type IV 2013-02-15 no assertion criteria provided literature only

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