rs565866662

Variant names:

• chr10-93064519-T-TCCATGCA
• rs565866662
• NM_183374.3:c.845_851dupCCATGCA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_183374.3(CYP26C1):​c.845_851dupCCATGCA​(p.Gln284HisfsTer129) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,613,456 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (7 hom.)
• Consequence: CYP26C1 NM_183374.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2 B:2
• Conservation: PhyloP100: 2.91

Genes affected

CYP26C1 (HGNC:20577): (cytochrome P450 family 26 subfamily C member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This enzyme is involved in the catabolism of all-trans- and 9-cis-retinoic acid, and thus contributes to the regulation of retinoic acid levels in cells and tissues. This gene is adjacent to a related gene on chromosome 10q23.33. [provided by RefSeq, Jul 2008]

ENSG00000285846 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP26C1	NM_183374.3	c.845_851dupCCATGCA	p.Gln284HisfsTer129	frameshift_variant	Exon 4 of 6	ENST00000651965.1	NP_899230.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP26C1	ENST00000651965.1	c.845_851dupCCATGCA	p.Gln284HisfsTer129	frameshift_variant	Exon 4 of 6		NM_183374.3	ENSP00000498424.1
ENSG00000285846	ENST00000648258.1	n.875_881dupCCATGCA		non_coding_transcript_exon_variant	Exon 1 of 4
CYP26C1	ENST00000624358.3	n.*1117-63_*1117-57dupCCATGCA		intron_variant	Intron 3 of 5	2		ENSP00000485098.1

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 311 AN: 152214 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00885

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00211 AC: 529 AN: 250796 Hom.: 1 AF XY: 0.00218 AC XY: 295 AN XY: 135520

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00716

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00252 AC: 3688 AN: 1461124 Hom.: 7 Cov.: 30 AF XY: 0.00237 AC XY: 1719 AN XY: 726788

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00647

Gnomad4 NFE exome AF: 0.00290

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00204 AC: 311 AN: 152332 Hom.: 1 Cov.: 33 AF XY: 0.00236 AC XY: 176 AN XY: 74484

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00885

Gnomad4 NFE AF: 0.00281

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.00141

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Focal facial dermal dysplasia type IV Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 20, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Jan 01, 2024	PVS1, PS3, PS4, BS1 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 15, 2013	- -

not provided Pathogenic:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CYP26C1: PVS1, PM2, PM3, PP4 -

CYP26C1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2024

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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 20, 2018

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. -

Optic nerve hypoplasia Benign:1

Likely benign, criteria provided, single submitter

research

Rare Disease Group, Clinical Genetics, Karolinska Institutet

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs565866662; hg19: chr10-94824276;