Submissions for variant NM_000500.7(CYP21A2):c.955C>T (p.Gln319Ter)

gnomAD frequency: 0.00339  dbSNP: rs7755898

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000711391	SCV000330930	pathogenic	not provided	2017-08-03	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000711391	SCV000841754	pathogenic	not provided	2023-06-07	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. Frequency data for this variant in the general population cannot be distinguished from that of the CYP21P pseudogene, and are therefore uninformative in assessment of variant pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is also referred to by codon 318 in published literature. This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2, suggesting this variant is also pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant caused a marked decrease in 21-hydroxylase mRNA levels (PMID: 3267225).
Myriad Genetics, Inc.	RCV000012951	SCV001193783	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2019-12-17	criteria provided, single submitter	clinical testing	NM_000500.7(CYP21A2):c.955C>T(Q319*) is classified as pathogenic in the context of congenital adrenal hyperplasia, CYP21A2-related and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 14715874, 3267225, 23359698 and 23769969. Classification of NM_000500.7(CYP21A2):c.955C>T(Q319*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Centogene AG - the Rare Disease Company	RCV000012951	SCV001424397	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency		criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000711391	SCV001449835	pathogenic	not provided	2015-11-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000711391	SCV001469966	pathogenic	not provided	2023-06-07	criteria provided, single submitter	clinical testing	The CYP21A2 c.955C>T (p.Gln319*) variant (also known as Q319X or Q318X) causes the premature termination of CYP21A2 protein synthesis. In the published literature, this variant has been reported as usually being associated with a salt-wasting CAH phenotype (PMIDs: 30995443 (2019), 30048636 (2018), 26804566 (2016), 23269230 (2013), 15858147 (2005), 8034294 (1994), 3267225 (1988)). The frequency of this variant in the general population, 0.00027 (9/33386 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Baylor Genetics	RCV000012951	SCV001524847	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2019-12-19	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000012951	SCV001984016	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2020-02-11	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000711391	SCV002018107	pathogenic	not provided	2023-03-02	criteria provided, single submitter	clinical testing
DASA	RCV000012951	SCV002107127	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2022-03-05	criteria provided, single submitter	clinical testing	The c.955C>T;p.(Gln319*) variant creates a premature translational stop signal in the CYP21A2 gene. It is expected to result in an absent or disrupted protein product - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 3267225) - PS3. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar: 12169; PMID: 20301350; PMID: 3267225; PMID: 12220458; PMID: 29715434; PMID: 28819757; PMID: 12220458; PMID: 28392195) - PS4. The p.(Gln319*) was detected in trans with a pathogenic variant (PMID: 26804566) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222348	SCV002500529	pathogenic	Congenital adrenal hyperplasia	2022-03-20	criteria provided, single submitter	clinical testing	Variant summary: CYP21A2 c.955C>T (p.Gln319X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.0001 in 249104 control chromosomes. c.955C>T has been widely reported in the literature in multiple individuals affected with Congenital Adrenal Hyperplasia (example, Elmougy_2021, New_2013). These data indicate that the variant is very likely to be associated with disease. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000711391	SCV002502921	pathogenic	not provided	2022-03-24	criteria provided, single submitter	clinical testing
3billion	RCV000012951	SCV002521233	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.036%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000012169 / PMID: 3267225 ). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000012951	SCV002557086	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital adrenal hyperplasia, due to 21-hydroxylase deficiency (MIM#201910) and nonclassic type hyperandrogenism, due to 21-hydroxylase deficiency (MIM#201910). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (523 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as one of the most frequent disease-causing CYP21A2 variants. (ClinVar, PMIDs: 31586465, 32616876) (SP) 1206 - This variant has been shown to be paternally inherited (LABID/by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Invitae	RCV000711391	SCV003332125	pathogenic	not provided	2022-11-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln319*) in the CYP21A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP21A2 are known to be pathogenic (PMID: 10857554). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This premature translational stop signal has been observed in individual(s) with classic salt-wasting, simple virilizing, and non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 3267225, 23359698, 25538881, 26804566, 30995443). This variant is also known as p.Q318X. ClinVar contains an entry for this variant (Variation ID: 12169). For these reasons, this variant has been classified as Pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000012951	SCV004048452	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency		criteria provided, single submitter	clinical testing	The c.955C>T (p.Gln319Ter) stop gained variant in CYP21A2 gene has been reported previously in patients affected with adrenal hyperplasia (Doleschall M. et al., 2017). The p.Gln319Ter variant is reported with the allele frequency (0.01%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change in CYP21A2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003924828	SCV004746566	pathogenic	CYP21A2-related condition	2024-02-06	criteria provided, single submitter	clinical testing	The CYP21A2 c.955C>T variant is predicted to result in premature protein termination (p.Gln319*). This is a common deleterious variant, which likely originated from the pseudogene CYP21A1P via gene conversion. As a nonsense variant resulting in a null allele, this variant is associated with salt-wasting (SW) congenital adrenal hyperplasia (CAH) (also known as Q318X; see for example at New et al. 2013. PubMed ID: 23359698; Finkielstain et al. 2011. PubMed ID: 20926536). This variant is interpreted as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000012951	SCV004804833	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2024-03-17	criteria provided, single submitter	research
OMIM	RCV000012951	SCV000033195	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2002-08-01	no assertion criteria provided	literature only
GeneReviews	RCV000012951	SCV000086806	not provided	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency		no assertion provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000012951	SCV000854658	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	2018-04-27	no assertion criteria provided	clinical testing
Lifecell International Pvt. Ltd	RCV000012951	SCV001482473	pathogenic	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency		no assertion criteria provided	clinical testing	The variant in exon 8 of the CYP21A2 gene c.955C>T;p.Gln319Ter (NM_000500.7) also know as Q318*. This variant was observed in a proband with an increased level of 17-OHP enzyme (>287.3 nmol/L) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. The observed variant has a minor allele frequency of 0.4% in gnomAD database and not reported in 1000 genome database.The reference base is conserved across the species and in-silico predictions by CADD is deleterious. The gene CYP21A2 has a low rate of benign loss of function variants as indicated by a high LoF variants Z-Score of 2.86. The p.Gln319Ter variant is a loss of function variant in the gene CYP21A2, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_000491.4:p.Trp20Ter and 4 others. There is another pathogenic loss of function variant 165 residues downstream of the variant p.Gln319Ter.This variant has previously been reported for adrenal hyperplasia by Doleschall M et al.,2017-PMID: 28401898; Concolino P. et al., 2020-PMID: 32185686; Kharrat M et al., 2004- PMID: 21532487 and Globerman H et al., 1988-PMID: 3267225).
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000711391	SCV001800361	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000711391	SCV001952694	pathogenic	not provided		no assertion criteria provided	clinical testing