chr11-71435461-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001360.3(DHCR7):c.1342G>A(p.Glu448Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000117 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E448Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001360.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.1342G>A | p.Glu448Lys | missense_variant | 9/9 | ENST00000355527.8 | |
DHCR7 | NM_001163817.2 | c.1342G>A | p.Glu448Lys | missense_variant | 9/9 | ||
DHCR7 | XM_011544777.3 | c.*105G>A | 3_prime_UTR_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.1342G>A | p.Glu448Lys | missense_variant | 9/9 | 1 | NM_001360.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000362 AC: 9AN: 248898Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135220
GnomAD4 exome AF: 0.000125 AC: 182AN: 1460304Hom.: 0 Cov.: 30 AF XY: 0.000127 AC XY: 92AN XY: 726534
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74342
ClinVar
Submissions by phenotype
Smith-Lemli-Opitz syndrome Pathogenic:8Other:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 12, 2019 | NM_001360.2(DHCR7):c.1342G>A(E448K) is classified as likely pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 16181459, 10995508 and 10814720. Classification of NM_001360.2(DHCR7):c.1342G>A(E448K) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 15, 2003 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Daryl Scott Lab, Baylor College of Medicine | Feb 01, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 448 of the DHCR7 protein (p.Glu448Lys). This variant is present in population databases (rs80338864, gnomAD 0.007%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10602371, 10995508, 12270273, 12949967). ClinVar contains an entry for this variant (Variation ID: 6792). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 30, 2017 | Variant summary: The DHCR7 c.1342G>A (p.Glu448Lys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/117588 control chromosomes at a frequency of 0.0000085, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). The variant has been reported in numerous SLOS patients both in the homozygous and compound heterozygous state, and is known as a common disease variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2022 | Published functional studies demonstrate that the E448K variant reduced protein stability and expression (Witsch-Baumgartner et al., 2000); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10602371, 10814720, 16181459, 12070263, 10995508, 12949967, 22975760, 10677299, 28166604, 27415407, 20301322, 16207203, 12270273, 34426522, 31589614) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 13, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at