rs80338864
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The ENST00000355527.8(DHCR7):āc.1342G>Cā(p.Glu448Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,612,504 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. E448K) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000355527.8 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.1342G>C | p.Glu448Gln | missense_variant | 9/9 | ENST00000355527.8 | NP_001351.2 | |
DHCR7 | NM_001163817.2 | c.1342G>C | p.Glu448Gln | missense_variant | 9/9 | NP_001157289.1 | ||
DHCR7 | XM_011544777.3 | c.*105G>C | 3_prime_UTR_variant | 9/9 | XP_011543079.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.1342G>C | p.Glu448Gln | missense_variant | 9/9 | 1 | NM_001360.3 | ENSP00000347717 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248898Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135220
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460304Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726534
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74342
ClinVar
Submissions by phenotype
Smith-Lemli-Opitz syndrome Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 09, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 09, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 448 of the DHCR7 protein (p.Glu448Gln). This variant is present in population databases (no rsID available, gnomAD 0.009%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10677299). ClinVar contains an entry for this variant (Variation ID: 554965). 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 DHCR7 protein function with a positive predictive value of 95%. This variant disrupts the p.Glu448 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10602371, 10995508, 12270273, 12949967). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2022 | Reported in a patient with SLOS in published literature (Witsch-Baumgartner et al., 2000); it is unclear whether a second variant was identified; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11001806, 12914579, 10677299, 11175299, 16207203, 15670717, 11111101, 23042628, 11241839, 11767235) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 04, 2024 | Variant summary: DHCR7 c.1342G>C (p.Glu448Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248898 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1342G>C has been reported in the literature as a non-informative genotype (second allele not specified) in at-least one individual affected with Smith-Lemli-Opitz Syndrome (example, Witsch-Baumgartner_2000) and continues to be cited by others. These data do not allow any conclusion about variant significance. Additionally, one variant at the Glu448 residue has been reported as associated with disease (c.1342G>A p.Glu448Lys), suggesting that this codon might be functionally important. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 10677299). ClinVar contains an entry for this variant (Variation ID: 554965). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at