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

gnomAD frequency: 0.00212  dbSNP: rs565866662

Total submissions: 9

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000968474	SCV001115932	likely benign	not provided	2019-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000968474	SCV003935703	pathogenic	not provided	2024-09-13	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 (PMID: 23161670); Frameshift variant predicted to result in abnormal protein length as the last 239 amino acid(s) are replaced with 128 different amino acid(s); This variant is associated with the following publications: (PMID: 32040484, 34426522, 23161670, 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
Fulgent Genetics, Fulgent Genetics	RCV002285162	SCV005683166	uncertain significance	Focal facial dermal dysplasia type IV	2024-02-20	criteria provided, single submitter	clinical testing
Daryl Scott Lab, Baylor College of Medicine	RCV002285162	SCV005871346	likely pathogenic	Focal facial dermal dysplasia type IV	2024-01-01	criteria provided, single submitter	clinical testing	PVS1, PS3, PS4, BS1
OMIM	RCV002285162	SCV000056850	pathogenic	Focal facial dermal dysplasia type IV	2013-02-15	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004758039	SCV005345178	pathogenic	CYP26C1-related disorder	2024-03-25	no assertion criteria provided	clinical testing	The CYP26C1 c.845_851dup7 variant is predicted to result in a frameshift and premature protein termination (p.Gln284Hisfs*129). This variant was reported in the compound heterozygous or homozygous state in multiple individuals with focal facial dermal dysplasia IV (Slavotinek et al. 2013. PubMed ID: 23161670, described as c.844_851dupCCATGCA; Lee et al. 2018. PubMed ID: 29263414). This variant is reported in 0.70% of alleles in individuals of European (Finnish) descent in gnomAD. This variant has also been observed in the heterozygous state in an individual with optic nerve hypoplasia (Table 2, Dahl et al. 2020. PubMed ID: 32040484). Frameshift variants in CYP26C1 are expected to be pathogenic. This variant is interpreted as pathogenic.