rs368944209
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000497.4(CYP11B1):āc.1112A>Gā(p.Glu371Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,714 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E371K) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000497.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP11B1 | NM_000497.4 | c.1112A>G | p.Glu371Gly | missense_variant | 6/9 | ENST00000292427.10 | |
CYP11B1 | NM_001026213.1 | c.1112A>G | p.Glu371Gly | missense_variant | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP11B1 | ENST00000292427.10 | c.1112A>G | p.Glu371Gly | missense_variant | 6/9 | 1 | NM_000497.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249324Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134996
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461714Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727176
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 28, 2022 | ClinVar contains an entry for this variant (Variation ID: 554618). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects CYP11B1 function (PMID: 8768848). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP11B1 protein function. This missense change has been observed in individual(s) with congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency (PMID: 8768848). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs368944209, gnomAD 0.007%). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 371 of the CYP11B1 protein (p.Glu371Gly). - |
CYP11B1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 07, 2022 | The CYP11B1 c.1112A>G variant is predicted to result in the amino acid substitution p.Glu371Gly. This substitution was predicted to disrupt the ion pair R374-E371, which is responsible for maintaining the heme-binding site (Khattab et al. 2017. PubMed ID: 28228528). In the compound heterozygous state with a frameshift variant, this variant was reported in an individual with 11-beta-hydroxylase deficiency (Geley et al. 1996. PubMed ID: 8768848). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-143957137-T-C). This variant is interpreted as likely pathogenic. - |
Deficiency of steroid 11-beta-monooxygenase Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 27, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at