ClinVar Miner

Submissions for variant NM_000500.9(CYP21A2):c.1174G>A (p.Ala392Thr) (rs202242769)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490344 SCV000267281 likely pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2016-03-18 criteria provided, single submitter reference population
Fulgent Genetics,Fulgent Genetics RCV000490344 SCV000893713 pathogenic Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000490344 SCV001137081 uncertain significance Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2019-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357310 SCV001552744 uncertain significance not provided no assertion criteria provided clinical testing The CYP21A2 p.Ala362Thr variant was identified as a compound heterozygous variant with a CYP21A2 p.V282L variant in a girl with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase; compound heterozygousity was confirmed through genotyping of the parents (Robins_2007_PMID:17119906). Whole exome sequencing of 43 children with a diagnosis of familial glucocorticoid deficiency identified the p.A362T variant as a heterozygous variant in one patient; a second variant was not identified (Chan_2015_PMID:26300845). The variant was identified in dbSNP (ID: rs202242769), ClinVar (classified as pathogenic by Fulgent Genetics and as likely pathogenic by Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 2320 of 266040 chromosomes (0 homozygous) at a frequency of 0.00872 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 846 of 29396 chromosomes (freq: 0.02878), East Asian in 153 of 19106 chromosomes (freq: 0.008008), European (non-Finnish) in 929 of 119756 chromosomes (freq: 0.007757), Ashkenazi Jewish in 75 of 10030 chromosomes (freq: 0.007478), Other in 41 of 6796 chromosomes (freq: 0.006033), European (Finnish) in 125 of 23452 chromosomes (freq: 0.00533), Latino in 114 of 34736 chromosomes (freq: 0.003282), and African in 37 of 22768 chromosomes (freq: 0.001625). The p.Ala362 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001357310 SCV001740033 pathogenic not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV001357310 SCV001800107 pathogenic not provided no assertion criteria provided clinical testing

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