VCV000012169.44 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(26)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Haplotype

NM_000500.7(CYP21A2):c.[844G>T;920_921insT;955C>T;1069C>T]

Identifiers

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

Variation ID: 12169 Accession: VCV000012169.44

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p21.33 6: 32040421 (GRCh38) [ NCBI UCSC ] 6: 32008198 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Nov 17, 2024	Mar 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000500.9:c.955C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000491.4:p.Gln319Ter	nonsense
NM_001128590.4:c.865C>T	NP_001122062.3:p.Gln289Ter	nonsense
NM_001368143.2:c.550C>T	NP_001355072.1:p.Gln184Ter	nonsense
NM_001368144.2:c.550C>T	NP_001355073.1:p.Gln184Ter	nonsense
NC_000006.12:g.32040421C>T
NC_000006.11:g.32008198C>T
NG_007941.3:g.7117C>T
NG_008337.2:g.73954G>A
NG_045215.1:g.2650C>T
LRG_829:g.7117C>T
LRG_829t1:c.955C>T	LRG_829p1:p.Gln319Ter

... more HGVS ... less HGVS

Protein change

Q319*, Q289*, Q184*

Other names

Q318*

Canonical SPDI

NC_000006.12:32040420:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00339

1000 Genomes Project 30x 0.03170

Links

ClinGen: CA341189 OMIM: 613815.0020 OMIM: 613815.0033 dbSNP: rs7755898 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CYP21A2		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	27	363
LOC106780800	-	-	-	GRCh38 GRCh38	-	305
TNXB		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	2370	2578

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency	Pathogenic (14)	criteria provided, multiple submitters, no conflicts	Mar 17, 2024	RCV000012951.29
not provided	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Jun 7, 2023	RCV000711391.22
Congenital adrenal hyperplasia	Pathogenic (1)	criteria provided, single submitter	Mar 20, 2022	RCV002222348.1
CYP21A2-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 12, 2024	RCV003924828.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 03, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000330930.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 3267225 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP21A2 Number of individuals with the variant: 7 Sex: mixed
Pathogenic (Mar 20, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Congenital adrenal hyperplasia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002500529.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (2) PubMed: 23359698‚ 32358738 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502921.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (36) PubMed: 3267225‚ 33715135‚ 31571129‚ 17164306‚ 33083013‚ 33710594‚ 30833958‚ 32647925‚ 10908170‚ 32903448‚ 28644547‚ 31980526‚ 31446012‚ 10408786‚ 21532487‚ 23769969‚ 19773403‚ 31637888‚ 28392195‚ 34540367‚ 11220701‚ 32272826‚ 25538881‚ 23359698‚ 26209023‚ 32367404‚ 25481255‚ 32714392‚ 9378109‚ 31586465‚ 26804566‚ 8741909‚ 25525159‚ 30995443‚ 31159521‚ 33240318 Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: yes Allele origin: germline	3billion Accession: SCV002521233.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Publications: PubMed (1) PubMed: 3267225 Comment: 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 … (more) 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. (less) Clinical Features: Hyponatremia (present) , Hyperkalemia (present) , Ambiguous genitalia (present) , Vomiting (present) , Elevated circulating 17-hydroxyprogesterone concentration (present)
Pathogenic (Nov 03, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003332125.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (6) PubMed: 10857554‚ 3267225‚ 23359698‚ 25538881‚ 26804566‚ 30995443 Comment: 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 … (more) 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. (less)
Pathogenic (Jun 07, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV001469966.3 First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024	Publications: PubMed (20) PubMed: 28392195‚ 26209023‚ 26804566‚ 3267225‚ 15858147‚ 28401898‚ 32185686‚ 30995443‚ 30889569‚ 30048636‚ 29386111‚ 8034294‚ 12384784‚ 19773403‚ 23269230‚ 21532487‚ 23769969‚ 25538881‚ 23359698‚ 25525159 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018107.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004804833.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Aug 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197684.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Jun 28, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center Accession: SCV005397349.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Publications: PubMed (5) PubMed: 23359698‚ 23142378‚ 31446012‚ 3267225‚ 26804566 Comment: This sequence variant is a single nucleotide substitution (C>T) in exon 8 of 10 of the CYP21A2 gene that changes the glutamine codon at position … (more) This sequence variant is a single nucleotide substitution (C>T) in exon 8 of 10 of the CYP21A2 gene that changes the glutamine codon at position 319 to an early termition sigl. This variant may be referred to as Q318X in the literature. This variant is predicted to generate a non-functiol allele through either the expression of a truncated protein or a loss of CYP21A2 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar 12169) that is one of the most commonly observed alleles observed in individuals affected by non-classical, simple virilizing, or salt wasting forms of congenital adrel hyperplasia due to 21-hydroxylase deficiency when in the homozygous, hemizygous, or compound heterozygous states (PMID: 3267225, 31446012, 23142378, 23359698, 26804566). This variant is present in 100 of 277730 alleles (0.0360%) in the gnomAD population dataset. A functiol study has confirmed that mR of this variant is rapidly degraded when expressed in mammalian cells (PMID: 3267225). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM3, PS4, PVS1 (less)
Pathogenic (Dec 17, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193783.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (4) PubMed: 14715874‚ 3267225‚ 23359698‚ 23769969 Comment: 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 … (more) 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. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital adrenal hyperplasia, due to 21-hydroxylase deficiency Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV001424397.1 First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020
Pathogenic (Nov 24, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449835.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 20
Pathogenic (Dec 19, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001524847.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Feb 11, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV001984016.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021
Pathogenic (Mar 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: yes Allele origin: germline	DASA Accession: SCV002107127.2 First in ClinVar: Mar 28, 2022 Last updated: Apr 02, 2022	Publications: PubMed (7) PubMed: 3267225‚ 20301350‚ 12220458‚ 29715434‚ 28819757‚ 28392195‚ 26804566 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 2 Sex: mixed Geographic origin: Brazil
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004048452.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: 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 … (more) 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. (less) Clinical Features: Clitoral hypertrophy (present) , Hypogonadism (present) , Abnormal circulating antimullerian hormone concentration (present) , Increased serum testosterone level (present)
Pathogenic (Jun 07, 2023)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000841754.4 First in ClinVar: Oct 20, 2018 Last updated: Jan 26, 2024	Publications: PubMed (20) PubMed: 28392195‚ 26209023‚ 26804566‚ 3267225‚ 15858147‚ 28401898‚ 32185686‚ 30995443‚ 30889569‚ 30048636‚ 29386111‚ 8034294‚ 12384784‚ 19773403‚ 23269230‚ 21532487‚ 23769969‚ 25538881‚ 23359698‚ 25525159 Comment: 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 … (more) 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). (less)
Pathogenic (Jul 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (Autosomal recessive inheritance) Affected status: no Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002557086.2 First in ClinVar: Aug 04, 2022 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 31586465‚ 32616876 Comment: 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 … (more) 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 hyperandrogenism nonclassic type 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) 0251 - This variant is heterozygous (according to Fulgent Genetics report). (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (523 heterozygotes, 0 homozygotes). (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has very 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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Aug 01, 2002)	no assertion criteria provided Method: literature only	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY, SALT-WASTING TYPE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033195.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 3267225‚ 12220458 Comment on evidence: Globerman et al. (1988) identified a T-to-C substitution at nucleotide 1994 in exon 8 of the CYP21A2 gene, resulting in a stop codon at position … (more) Globerman et al. (1988) identified a T-to-C substitution at nucleotide 1994 in exon 8 of the CYP21A2 gene, resulting in a stop codon at position 318 (Q318X). Individuals homozygous for this mutation have the salt-wasting form of 21-hydroxylase deficiency (201910) and no enzymatic activity. This mutation is normally present in the CYP21 pseudogene. In a Spanish population, Ezquieta et al. (2002) provided data on the contributions of gene conversion and founder effect to the distribution of the 2 most frequent severe point mutations of the CYP21A2 gene causing congenital adrenal hyperplasia: the 655G splicing mutation at intron 2 (613815.0006) and gln318-to-ter. Both mechanisms were found to contribute to the mutant alleles in different degrees. The 655G splicing mutation (accounting for 15.5% of alleles) seemed to be almost exclusively related to recent conversion events, whereas Q318X (accounting for 8.3% of alleles) was more likely to be due to the dissemination of remotely generated mutant alleles. (less)
Pathogenic (Apr 27, 2018)	no assertion criteria provided Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV000854658.1 First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Lifecell International Pvt. Ltd Accession: SCV001482473.2 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021	Comment: 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 … (more) 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). (less) Indication for testing: Decreased level of 17-OHP enzyme (>287.3 nmol/L) Ethnicity/Population group: Asian Geographic origin: India Testing laboratory: GTRL000507720 Testing laboratory interpretation: Pathogenic
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001800361.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Pathogenic (Jul 12, 2024)	no assertion criteria provided Method: clinical testing	CYP21A2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004746566.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The CYP21A2 c.955C>T variant is predicted to result in premature protein termination (p.Gln319). This is a common deleterious variant that likely originated from the pseudogene … (more) The CYP21A2 c.955C>T variant is predicted to result in premature protein termination (p.Gln319). This is a common deleterious variant that 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. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001952694.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (-)	no classification provided Method: literature only	Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000086806.2 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 20301350 BookShelf: NBK1171 BookShelf: NBK1171
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Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

This sequence variant is a single nucleotide substitution (C>T) in exon 8 of 10 of the CYP21A2 gene that changes the glutamine codon at position 319 to an early termition sigl. This variant may be referred to as Q318X in the literature. This variant is predicted to generate a non-functiol allele through either the expression of a truncated protein or a loss of CYP21A2 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar 12169) that is one of the most commonly observed alleles observed in individuals affected by non-classical, simple virilizing, or salt wasting forms of congenital adrel hyperplasia due to 21-hydroxylase deficiency when in the homozygous, hemizygous, or compound heterozygous states (PMID: 3267225, 31446012, 23142378, 23359698, 26804566). This variant is present in 100 of 277730 alleles (0.0360%) in the gnomAD population dataset. A functiol study has confirmed that mR of this variant is rapidly degraded when expressed in mammalian cells (PMID: 3267225). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM3, PS4, PVS1

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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).

Comment:

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 hyperandrogenism nonclassic type 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) 0251 - This variant is heterozygous (according to Fulgent Genetics report). (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (523 heterozygotes, 0 homozygotes). (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has very 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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

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).

Comment:

The CYP21A2 c.955C>T variant is predicted to result in premature protein termination (p.Gln319*). This is a common deleterious variant that 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Germline mutation analyses of malignant ground glass opacity nodules in non-smoking lung adenocarcinoma patients.	Mao W	PeerJ	2021	PMID: 34540367
A novel 9 bp deletion (c.1271_1279delGTGCCCGCG) in exon 10 of CYP21A2 gene causing severe congenital adrenal hyperplasia.	Anastasovska V	Endocrine	2021	PMID: 33715135
Molecular Analysis of 21-Hydroxylase Deficiency Reveals Two Novel Severe Genotypes in Affected Newborns.	Concolino P	Molecular diagnosis & therapy	2021	PMID: 33710594
Genetic profiling of CAH Egyptian children: rapid guide to clinical interpretation of common mutations.	Elmougy F	Journal of endocrinological investigation	2021	PMID: 32358738
Application of Next-Generation Sequencing for Genetic Diagnosis in Neonatal Intensive Care Units: Results of a Multicenter Study in China.	Zhu T	Frontiers in genetics	2020	PMID: 33240318
Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility.	Cheema H	NPJ genomic medicine	2020	PMID: 33083013
Primary Adrenocortical Insufficiency Case Series in the Neonatal Period: Genetic Etiologies Are More Common Than Expected.	Gao J	Frontiers in pediatrics	2020	PMID: 32903448
p.Gln318X and p.Val281Leu as the Major Variants of CYP21A2 Gene in Children with Idiopathic Premature Pubarche.	Soveizi M	International journal of endocrinology	2020	PMID: 32714392
Genotype-phenotype correlations in children and adolescents with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.	Dörr HG	Molecular and cellular pediatrics	2020	PMID: 32647925
EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency.	Baumgartner-Parzer S	European journal of human genetics : EJHG	2020	PMID: 32616876
An exome-first approach to aid in the diagnosis of primary ciliary dyskinesia.	Shamseldin HE	Human genetics	2020	PMID: 32367404
Simple virilising congenital adrenal hyperplasia in monozygotic twins: A rare report and review of previous cases.	Muthuvel B	Pediatric endocrinology, diabetes, and metabolism	2020	PMID: 32272826
A rare CYP21A2 haplotype clarifies the phenotype-genotype discrepancy in an Italian patient with Non Classical Congenital Adrenal Hyperplasia (NC-CAH).	Concolino P	Molecular biology reports	2020	PMID: 32185686
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
21-Hydroxylase deficiency: Mutational spectrum and Genotype-Phenotype relations analyses by next-generation sequencing and multiplex ligation-dependent probe amplification.	Turan I	European journal of medical genetics	2020	PMID: 31586465
Detection of a novel severe mutation affecting the CYP21A2 gene in a Chilean male with salt wasting congenital adrenal hyperplasia.	Arteaga E	Endocrine	2020	PMID: 31571129
Implementation of a Targeted Next-Generation Sequencing Panel for Constitutional Newborn Screening in High-Risk Neonates.	Lee H	Yonsei medical journal	2019	PMID: 31637888
Analysis of phenotypes and genotypes in 84 patients with 21-Hydroxylase deficiency in southern China.	Hou L	Steroids	2019	PMID: 31446012
[Clinical features and genetic characteristics of 33 patients with simple virilizing form of 21-hydroxylase deficiency].	Zeng LT	Zhonghua nei ke za zhi	2019	PMID: 31159521
Identification of novel and rare CYP21A2 variants in Chinese patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.	Xu J	Clinical biochemistry	2019	PMID: 30995443
CYP21A2 Gene Pathogenic Variants: A Multicenter Study on Genotype-Phenotype Correlation from a Portuguese Pediatric Cohort.	Santos-Silva R	Hormone research in paediatrics	2019	PMID: 30889569
Identification of the Germline Mutation Profile in Esophageal Squamous Cell Carcinoma by Whole Exome Sequencing.	Deng J	Frontiers in genetics	2019	PMID: 30833958
Clinical and molecular profile of newborns with confirmed or suspicious congenital adrenal hyperplasia detected after a public screening program implementation.	Kopacek C	Jornal de pediatria	2019	PMID: 29715434
Clinical presentation and mutational spectrum in a series of 166 patients with classical 21-hydroxylase deficiency from South China.	Su L	Clinica chimica acta; international journal of clinical chemistry	2018	PMID: 30048636
Modeling Congenital Adrenal Hyperplasia and Testing Interventions for Adrenal Insufficiency Using Donor-Specific Reprogrammed Cells.	Ruiz-Babot G	Cell reports	2018	PMID: 29386111
A genetic epidemiology study of congenital adrenal hyperplasia in Italy.	Gialluisi A	Clinical genetics	2018	PMID: 28644547
Clinical characteristics of Taiwanese children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency detected by neonatal screening.	Liu SY	Journal of the Formosan Medical Association = Taiwan yi zhi	2018	PMID: 28392195
Development of CYP21A2 Genotyping Assay for the Diagnosis of Congenital Adrenal Hyperplasia.	Prado MJ	Molecular diagnosis & therapy	2017	PMID: 28819757
A unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics.	Doleschall M	European journal of human genetics : EJHG	2017	PMID: 28401898
21-hydroxylase deficiency-induced congenital adrenal hyperplasia in 230 Chinese patients: Genotype-phenotype correlation and identification of nine novel mutations.	Wang R	Steroids	2016	PMID: 26804566
CYP21A2 genetics: When genotype does not fit phenotype.	Sani I	Clinical biochemistry	2016	PMID: 26209023
21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia.	Adam MP	-	2016	PMID: 20301350
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
Genetic defects of the CYP21A2 gene in girls with premature adrenarche.	Skordis N	Journal of endocrinological investigation	2015	PMID: 25481255
Phenotypic variability of hyperandrogenemia in females heterozygous for CYP21A2 mutations.	Neocleous V	Indian journal of endocrinology and metabolism	2014	PMID: 25538881
A case with combined rare inborn metabolic disorders: congenital adrenal hyperplasia and ornithine transcarbamylase deficiency.	Kim YM	Gene	2013	PMID: 23769969
Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency.	New MI	Proceedings of the National Academy of Sciences of the United States of America	2013	PMID: 23359698
Erroneous prenatal diagnosis of congenital adrenal hyperplasia owing to a duplication of the CYP21A2 gene.	Lekarev O	Journal of perinatology : official journal of the California Perinatal Association	2013	PMID: 23269230
Investigation of CYP21A2 mutations in Turkish patients with 21-hydroxylase deficiency and a novel founder mutation.	Toraman B	Gene	2013	PMID: 23142378
Detection of a frequent duplicated CYP21A2 gene carrying a Q318X mutation in a general population with quantitative PCR methods.	Kharrat M	Diagnostic molecular pathology : the American journal of surgical pathology, part B	2011	PMID: 21532487
Duplications of the functional CYP21A2 gene are primarily restricted to Q318X alleles: evidence for a founder effect.	Kleinle S	The Journal of clinical endocrinology and metabolism	2009	PMID: 19773403
Predisposition for de novo gene aberrations in the offspring of mothers with a duplicated CYP21A2 gene.	Baumgartner-Parzer SM	The Journal of clinical endocrinology and metabolism	2007	PMID: 17164306
Validation and clinical application of a locus-specific polymerase chain reaction- and minisequencing-based assay for congenital adrenal hyperplasia (21-hydroxylase deficiency).	Keen-Kim D	The Journal of molecular diagnostics : JMD	2005	PMID: 15858147
Molecular genetic analysis of Tunisian patients with a classic form of 21-hydroxylase deficiency: identification of four novel mutations and high prevalence of Q318X mutation.	Kharrat M	The Journal of clinical endocrinology and metabolism	2004	PMID: 14715874
Duplication of the CYP21A2 gene complicates mutation analysis of steroid 21-hydroxylase deficiency: characteristics of three unusual haplotypes.	Koppens PF	Human genetics	2002	PMID: 12384784
Gene conversion (655G splicing mutation) and the founder effect (Gln318Stop) contribute to the most frequent severe point mutations in congenital adrenal hyperplasia (21-hydroxylase deficiency) in the Spanish population.	Ezquieta B	Clinical genetics	2002	PMID: 12220458
Molecular characterization of mutations in Indian children with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency.	Mathur R	Journal of pediatric endocrinology & metabolism : JPEM	2001	PMID: 11220701
Mutations in the CYP21 B gene in a Chilean population with simple virilizing congenital adrenal hyperplasia.	Fardella CE	Journal of endocrinological investigation	2000	PMID: 10908170
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency.	White PC	Endocrine reviews	2000	PMID: 10857554
A rapid screening for steroid 21-hydroxylase mutations in patients with congenital adrenal hyperplasia. Mutations in brief no. 247. Online.	Kapelari K	Human mutation	1999	PMID: 10408786
Conventional molecular diagnosis of steroid 21-hydroxylase deficiency using mismatched primers and polymerase chain reaction.	Tajima T	Endocrine research	1997	PMID: 9378109
Who is a carrier? Detection of unsuspected mutations in 21-hydroxylase deficiency.	Witchel SS	American journal of medical genetics	1996	PMID: 8741909
Characterization of mutations on the rare duplicated C4/CYP21 haplotype in steroid 21-hydroxylase deficiency.	Wedell A	Human genetics	1994	PMID: 8034294
Nonsense mutation causing steroid 21-hydroxylase deficiency.	Globerman H	The Journal of clinical investigation	1988	PMID: 3267225
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CYP21A2	-	-	-	-
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Text-mined citations for rs7755898 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs7755898 ...