chr2-218812266-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5
The NM_000784.4(CYP27A1):c.491G>C(p.Arg164Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000632 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R164Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000784.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP27A1 | NM_000784.4 | c.491G>C | p.Arg164Pro | missense_variant | 3/9 | ENST00000258415.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP27A1 | ENST00000258415.9 | c.491G>C | p.Arg164Pro | missense_variant | 3/9 | 1 | NM_000784.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251450Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135898
GnomAD4 exome AF: 0.0000602 AC: 88AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.0000536 AC XY: 39AN XY: 727236
GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74364
ClinVar
Submissions by phenotype
not provided Uncertain:7
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 11, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 05, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 12, 2023 | Reported as a heterozygous variant in a patient with an inborn error of bile acid metabolism in the published literature; however, a second variant in CYP27A1 was not reported (Chen et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30366773) - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 24, 2023 | - - |
Cholestanol storage disease Uncertain:2Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 17, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
CYP27A1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 18, 2023 | The CYP27A1 c.491G>C variant is predicted to result in the amino acid substitution p.Arg164Pro. This variant has been reported in a patient with an inborn error of bile acid metabolism; however, this patient lacked a second variant in CYP27A1 and also had a homozygous variant in the AKR1D1 gene and a heterozygous variant in the ABCC3 gene (Patient 04 in Table 4, Chen et al 2018. PubMed ID: 30366773). This variant is reported in 0.065% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-219676989-G-C), which may be too common for a pathogenic variant. This variant has conflicting interpretations in ClinVar regarding its pathogenicity ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/498357). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 05, 2023 | The c.491G>C (p.R164P) alteration is located in exon 3 (coding exon 3) of the CYP27A1 gene. This alteration results from a G to C substitution at nucleotide position 491, causing the arginine (R) at amino acid position 164 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at