ClinVar Miner

Submissions for variant NM_000500.9(CYP21A2):c.844G>T (p.Val282Leu) (rs6471)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000210728 SCV000263011 pathogenic Inborn genetic diseases 2014-06-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Athena Diagnostics Inc RCV000711385 SCV000841748 pathogenic not provided 2018-05-30 criteria provided, single submitter clinical testing
Counsyl RCV000012934 SCV000678075 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2015-12-22 criteria provided, single submitter clinical testing NM_000500.7(CYP21A2):c.844G>T(V282L, aka V281L) is a non-classic 21-hydroxylase-deficient congenital adrenal hyperplasia mutation.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000711385 SCV000854780 pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000012934 SCV000611260 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2017-05-18 criteria provided, single submitter clinical testing
GeneReviews RCV000012934 SCV000086803 pathologic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2013-08-29 no assertion criteria provided curation Converted during submission to Pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar RCV000012934 SCV000680185 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2017-10-26 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000012934 SCV000494239 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2016-06-27 criteria provided, single submitter clinical testing The well-known c.844G>T (p.Val282Leu) missense variant is frequently observed in individuals affected with non-classical congenital adrenal hyperplasia (GeneReviews: Nimkarn et al., 2016, , Eziquieta et al. 2010, Stikkelbroeck et al. 2003, Skordis et al. 2015, Ramazani et al. 2008). New et al. (2013) reported that 98% (n = 497) of individuals with Non-classical CAH harbored this variant and its frequency was very high in affected individuals from the Ashkenazi Jewish population. Although this variant is associated with non-classical CAH, individuals with classical CAH were also found to have this variant (New et al. 2013). Functional studies found that co-expression of this mutant protein and wild-type (WT) protein results in a dominant negative effect on the enzymatic activity of WT protein (Felix-Lopez et al. 2003). Other studies indicate reduced enzyme activity with the p.Val281Leu allele (Wu and Chung 1991, Haider et al. 2013). The variant is observed in the population databases at a frequency below expected for the carrier rate based on prevalence of disease (ExAC, 1000 Genomes, ESP). Reputable clinical labs have interpreted this variant as pathogenic (Partners HealthCare and Ambry Genetics). In summary, this mutation meets the criteria for a Pathogenic variant for Adrenal hyperplasia, congenital, due to 21 – hydroxylase deficiency. We have confirmed this finding in our laboratory using Sanger sequencing.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000012934 SCV000245595 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2014-10-17 criteria provided, single submitter clinical testing The p.Val282Leu variant (NM_000500.7 c.844G>T) (also referred to as p.Val281Leu in the literature) in CYP21A2 is a well-established pathogenic variant and has b een reported in numerous individuals with non-classical congenital adrenal hyper plasia (CAH) (Marino 2001, Ezquieta 2010, New 2013). This variant has also been reported in ClinVar (Variation ID#12151), as pathogenic. This variant has been i dentified in 2.0% (175/8588) of Ashkenazi Jewish chromosomes by the Genome Aggre gation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs6471), althou gh data at this locus may not be reliable due to high homology with a pseudogene . In vitro functional studies indicate that the p.Val282Leu variant may impact protein function (Tusie-Luna 1990, Barbaro 2015). In summary, this variant meets our criteria to be classified as pathogenic for non-classical CAH in an autosom al recessive manner based on observations in individuals with this disease and f unctional evidence. ACMG/AMP Criteria applied: PM3 (upgraded to strong based on multiple occurrences), PS3, PP5 (Richards 2015).
OMIM RCV000012934 SCV000033175 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 1998-07-01 no assertion criteria provided literature only
OMIM RCV000012935 SCV000033176 pathogenic Adenoma, cortisol-producing 1998-07-01 no assertion criteria provided literature only
OMIM RCV000012936 SCV000033177 pathogenic Carcinoma, adrenocortical, androgen-secreting 1998-07-01 no assertion criteria provided literature only

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