ClinVar Miner

Submissions for variant NM_000784.4(CYP27A1):c.526del (p.Asp176fs)

dbSNP: rs765512351
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000307005 SCV000427466 likely pathogenic Cholestanol storage disease 2017-04-27 criteria provided, single submitter clinical testing The CYP27A1 c.525delG (p.Asp176MetfsTer6) variant, also known as c.526delG, results in a frameshift, and is predicted to result in premature termination of the protein. The p.Asp176MetfsTer6 variant has been reported in four studies in which it is found in a total of five individuals with cerebrotendinous xanthomatosis, including two siblings, all of whom were homozygous for the variant (Verrips et al. 1996; Clayton et al. 2002; Shah et al. 2012; Dutta et al. 2015). The variant has also been reported in a heterozygous state in one unaffected individual. Control data are unavailable for this variant which is reported at a frequency of 0.00012 in the South Asian population of the Exome Aggregation Consortium, but this is based on two alleles only in a region of good sequence coverage so the variant is presumed rare. Due to the potential impact of frameshift variants and the supporting evidence from the literature, the p.Asp176MetfsTer6 variant is classified as likely pathogenic for cerebrotendinous xanthomatosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000307005 SCV001586476 pathogenic Cholestanol storage disease 2023-05-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp176Metfs*6) in the CYP27A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP27A1 are known to be pathogenic (PMID: 9392430, 10775536, 26937392). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 334367). This variant is also known as c.546del. This premature translational stop signal has been observed in individuals with cerebrotendinous xanthomatosis (PMID: 8931710, 26937392). This variant is present in population databases (rs765512351, gnomAD 0.03%).
Fulgent Genetics, Fulgent Genetics RCV000307005 SCV002801302 pathogenic Cholestanol storage disease 2022-01-05 criteria provided, single submitter clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV000307005 SCV002820230 pathogenic Cholestanol storage disease criteria provided, single submitter clinical testing This variant causes a frameshift starting with codon Aspartic Acid 176, changes this amino acid to Methionine residue, and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Asp176MetfsTer6. This variant has been previously reported in affected patients and has segregated with disease (Dutta AK et al, Shah K et al, Clayton PT et al). The variant has been reported to ClinVar as Pathogenic. The p.Asp176MetfsTer6 variant is novel (not in any individuals) in 1000 Genomes and is present at a frequency of 0.00012 in South Asian population in the gnomad database. The variant is predicted to cause loss of function due to protein truncation. Loss of function variants have been previously reported to be disease causing. Hence the above variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000307005 SCV003819406 pathogenic Cholestanol storage disease 2022-03-21 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003422309 SCV004117517 pathogenic CYP27A1-related condition 2022-09-22 criteria provided, single submitter clinical testing The CYP27A1 c.526delG variant is predicted to result in a frameshift and premature protein termination (p.Asp176Metfs*6). This variant was reported in the homozygous state in individuals with cerebrotendinous xanthomatosis (reported as G deletion at position 546 or 547 in Verrips et al. 1996. PubMed ID: 8931710; Dutta et al. 2015. PubMed ID: 26937392). This variant is reported in 0.026% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-219677022-CG-C). Frameshift variants in CYP27A1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics RCV000307005 SCV004192641 pathogenic Cholestanol storage disease 2023-10-24 criteria provided, single submitter clinical testing
GeneReviews RCV000307005 SCV000087197 pathologic Cholestanol storage disease 2013-08-01 no assertion criteria provided curation Converted during submission to Pathogenic.
Counsyl RCV000307005 SCV001132161 pathogenic Cholestanol storage disease 2017-10-17 no assertion criteria provided clinical testing
Natera, Inc. RCV000307005 SCV002078772 pathogenic Cholestanol storage disease 2021-01-19 no assertion criteria provided clinical testing

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