rs80338860
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001360.3(DHCR7):c.1054C>T(p.Arg352Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,611,952 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R352Q) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.1054C>T | p.Arg352Trp | missense_variant | 9/9 | ENST00000355527.8 | |
DHCR7 | NM_001163817.2 | c.1054C>T | p.Arg352Trp | missense_variant | 9/9 | ||
DHCR7 | XM_011544777.3 | c.1188C>T | p.Ser396= | synonymous_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.1054C>T | p.Arg352Trp | missense_variant | 9/9 | 1 | NM_001360.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152242Hom.: 0 Cov.: 35
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 248974Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135220
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1459710Hom.: 0 Cov.: 37 AF XY: 0.0000193 AC XY: 14AN XY: 725960
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152242Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1AN XY: 74380
ClinVar
Submissions by phenotype
Smith-Lemli-Opitz syndrome Pathogenic:7Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 16, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 10, 2018 | Variant summary: DHCR7 c.1054C>T (p.Arg352Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 275158 control chromosomes (gnomAD). The variant, c.1054C>T, has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Fitzky_1998, Witsch-Baumgartner_2001, Waterham_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence showing more than 90% reduction in protein expression associated with this variant (Fitzky_1998). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2001 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 352 of the DHCR7 protein (p.Arg352Trp). This variant is present in population databases (rs80338860, gnomAD 0.004%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 9653161, 15521979, 18006960; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6787). 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%. Experimental studies have shown that this missense change affects DHCR7 function (PMID: 9653161). This variant disrupts the p.Arg352 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16044199, 17441222, 21696385). 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jun 14, 2015 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 19, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2022 | Expression studies found that this variant is associated with significantly decreased DHCR7 protein expression (Fitzky BU et al., 1998); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 10602371, 15952211, 16207203, 18006960, 16983147, 21696385, 17441222, 16044199, 20301322, 31840946, 22975760, 11175299, 15521979, 9653161, 25040602, 23042628) - |
DHCR7-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 30, 2023 | The DHCR7 c.1054C>T variant is predicted to result in the amino acid substitution p.Arg352Trp. This variant has been reported alone or with a second DHCR7 variant in individuals with Smith-Lemli-Opitz syndrome (see, for example, Fitzky et al 1998. PubMed ID: 9653161; Witsch-Baumgartner et al 2001. PubMed ID: 11175299; Pappu et al 2006. PubMed ID: 16983147). In vitro experimental studies suggest this variant impacts protein function (Fitzky et al 1998. PubMed ID: 9653161). Alternative nucleotide changes affecting the same amino acid (p.Arg352Gln, p.Arg352Leu) have also been reported in individuals with Smith-Lemli-Opitz syndrome (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299; Al-Owain et al. 2012. PubMed ID: 21696385). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-71146795-G-A). This variant is interpreted as pathogenic. - |
Microcephaly Uncertain:1
Uncertain significance, no assertion criteria provided | research | Department of Pediatrics, Samsung Medical Center, Samsung Medical Center | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at