6-32040421-C-T
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000500.9(CYP21A2):c.955C>T(p.Gln319*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000896 in 1,580,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000500.9 stop_gained
Scores
Clinical Significance
Conservation
Publications
- classic congenital adrenal hyperplasia due to 21-hydroxylase deficiencyInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
- classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting formInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing formInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000500.9. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CYP21A2 | NM_000500.9 | MANE Select | c.955C>T | p.Gln319* | stop_gained | Exon 8 of 10 | NP_000491.4 | ||
| CYP21A2 | NM_001128590.4 | c.865C>T | p.Gln289* | stop_gained | Exon 7 of 9 | NP_001122062.3 | |||
| CYP21A2 | NM_001368143.2 | c.550C>T | p.Gln184* | stop_gained | Exon 8 of 10 | NP_001355072.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CYP21A2 | ENST00000644719.2 | MANE Select | c.955C>T | p.Gln319* | stop_gained | Exon 8 of 10 | ENSP00000496625.1 | ||
| CYP21A2 | ENST00000435122.3 | TSL:2 | c.865C>T | p.Gln289* | stop_gained | Exon 7 of 9 | ENSP00000415043.2 | ||
| CYP21A2 | ENST00000479074.5 | TSL:3 | n.1013C>T | non_coding_transcript_exon | Exon 8 of 9 |
Frequencies
GnomAD3 genomes 0.00382 AC: 523AN: 136986Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.000104 AC: 26AN: 249104 AF XY: 0.0000815 show subpopulations
GnomAD4 exome AF: 0.000622 AC: 898AN: 1443134Hom.: 0 Cov.: 38 AF XY: 0.000684 AC XY: 491AN XY: 717354 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
Age Distribution
GnomAD4 genome 0.00378 AC: 518AN: 137118Hom.: 0 Cov.: 33 AF XY: 0.00381 AC XY: 255AN XY: 67010 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
Age Distribution
ClinVar
Submissions by phenotype
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Pathogenic:16Other:1
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
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).
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.
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.036%). Predicted Consequence/Location: 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 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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.
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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
PVS1,PS3,PM3
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.
not provided Pathogenic:10
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.
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)). In multiple individuals with clinical features associated with this gene, this variant has been seen in trans with other recessive pathogenic variants in CYP21A2, suggesting this variant is also pathogenic. In some published literature, this variant is referred to as p.Q318X. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 3267225)
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.
CYP21A2-related disorder Pathogenic:1
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.
Congenital adrenal hyperplasia Pathogenic:1
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.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at