rs376230356
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000784.4(CYP27A1):c.380G>A(p.Arg127Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,014 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000784.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP27A1 | NM_000784.4 | c.380G>A | p.Arg127Gln | missense_variant | 2/9 | ENST00000258415.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP27A1 | ENST00000258415.9 | c.380G>A | p.Arg127Gln | missense_variant | 2/9 | 1 | NM_000784.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152138Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251346Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135832
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461876Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 727236
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152138Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2AN XY: 74320
ClinVar
Submissions by phenotype
Cholestanol storage disease Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 127 of the CYP27A1 protein (p.Arg127Gln). This variant is present in population databases (rs376230356, gnomAD 0.004%). This missense change has been observed in individual(s) with cerebrotendinous xanthomatosis (CTX) (PMID: 8730343, 10775536; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Arg94Gln. ClinVar contains an entry for this variant (Variation ID: 65866). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYP27A1 protein function. This variant disrupts the p.Arg127 amino acid residue in CYP27A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10430841, 10775536, 23659550, 27455001, 28623566). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 08, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 19, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | curation | GeneReviews | Aug 01, 2013 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 05, 2023 | PP1, PP4, PM2, PM3_strong, PM5 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at