ClinVar Miner

Submissions for variant NM_000500.9(CYP21A2):c.1447C>T (p.Pro483Ser) (rs776989258)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000732097 SCV000860003 pathogenic not provided 2018-05-08 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826138 SCV000967662 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2017-10-25 criteria provided, single submitter clinical testing The p.Pro483Ser (NM_000500.7 c.1447C>T) variant in CYP21A2 (also described as p. Pro482Ser, legacy) has been reported in at least 13 heterozygous individuals who se second allele was not identified and 25 compound heterozygous individual with non-classical congenital adrenal hyperplasia and related disorders (Barbaro 200 4, Finklestain 2011, Neocleous 2014, Skordis 2015, Fernandez 2015, Balsamo 2000, Di Pasquale 2005, Concolino 2011, Skordis 2011, Marino 2011, Malikova 2012, and Livadas 2015). It should be noted that this variant segregated in 2 siblings (1 of which was asymptomatic) in 2 families (Barbaro 2014). Although a second var iant was not identified in a large number of individuals, the allele frequency i n cases is statistically significantly increased compared to the general populat ion (18/1534 vs 82/114,652 European gnomAD, p<0.0001 (Chi-Square with Yates corr ection) suggesting a causative role. In vitro functional studies suggest that th e p.Pro483 variant may be a mild mutation with reduced activity (Barbaro 2004 an d Barbaro 2015). This variant has been identified in 0.071% (82/114734) of Europ ean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org; dbSNP rs776989258), though this frequency is low enough to be cons istent with a recessive carrier frequency. In summary, although additional studi es are required to fully establish its clinical significance, the p.Pro483Ser va riant is pathogenic for non-classical congenital adrenal hyperplasia in an autos omal recessive manner based upon statistically significant case observations in affected individuals and functional studies. It also should be noted that this v ariant is considered to confer a mild phenotype. ACMG/AMP Criteria applied: PM3 _VeryStrong; PS3_Moderate; PS4_Moderate; PP3 (Richards 2015).

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