rs781687341
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_001360.3(DHCR7):c.1328G>T(p.Arg443Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,612,354 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. R443C) has been classified as Pathogenic.
Frequency
Consequence
NM_001360.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.1328G>T | p.Arg443Leu | missense_variant | Exon 9 of 9 | ENST00000355527.8 | NP_001351.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248902Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135162
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1460138Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12AN XY: 726430
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74362
ClinVar
Submissions by phenotype
Smith-Lemli-Opitz syndrome Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 443 of the DHCR7 protein (p.Arg443Leu). This variant is present in population databases (rs781687341, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DHCR7-related conditions. ClinVar contains an entry for this variant (Variation ID: 1066741). 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.Arg443 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously reported as pathogenic or benign in association with Smith-Lemli-Opitz syndrome to our knowledge (PMID: 34308104); This variant is associated with the following publications: (PMID: 10677299, 34308104) -
DHCR7-related disorder Pathogenic:1
The DHCR7 c.1328G>T variant is predicted to result in the amino acid substitution p.Arg443Leu. This variant has been reported in at least one individual with acute lymphoblastic leukemia (Kim et al. 2021. PubMed ID: 34308104. Table S2). Additionally, different missense substitutions at this same codon (p.Arg443Cys, p.Arg443His, p.Arg443Pro) have been reported in individuals with Smith-Lemli-Opitz syndrome (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299; ClinVar ID: 1071907, 397519, 557359) suggesting that substitution of amino acid residue p.Arg443 is not tolerated. This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at