rs80338862
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000355527.8(DHCR7):āc.1228G>Cā(p.Gly410Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,610,856 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G410S) has been classified as Pathogenic.
Frequency
Consequence
ENST00000355527.8 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.1228G>C | p.Gly410Arg | missense_variant | 9/9 | ENST00000355527.8 | NP_001351.2 | |
DHCR7 | NM_001163817.2 | c.1228G>C | p.Gly410Arg | missense_variant | 9/9 | NP_001157289.1 | ||
DHCR7 | XM_011544777.3 | c.1362G>C | p.Ser454= | synonymous_variant | 9/9 | XP_011543079.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.1228G>C | p.Gly410Arg | missense_variant | 9/9 | 1 | NM_001360.3 | ENSP00000347717 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 35
GnomAD4 exome AF: 0.0000206 AC: 30AN: 1458636Hom.: 0 Cov.: 85 AF XY: 0.0000179 AC XY: 13AN XY: 725740
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1AN XY: 74368
ClinVar
Submissions by phenotype
Smith-Lemli-Opitz syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Smith-Lemli-Opitz syndrome (MIM#270400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (18 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated 4th cytoplamic loop of the transmembrane domain (PMID: 10677299). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. A different variant in the same codon resulting in a change to a serine has been reported in multiple individuals with Smith-Lemli-Opitz syndrome (ClinVar). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in two individuals with Smith-Lemli-Opitz syndrome (PMID: 10677299, PMID: 29455191). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that this variant reduces protein expression. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 01, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 410 of the DHCR7 protein (p.Gly410Arg). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10677299, 29455191). ClinVar contains an entry for this variant (Variation ID: 1457187). 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.Gly410 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9653161, 12818773, 15896653). 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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 02, 2022 | Variant summary: DHCR7 c.1228G>C (p.Gly410Arg) results in a non-conservative amino acid change in the encoded protein sequence within a transmembrane domain (Witsch-Baumgartner_2000). A known pathogenic variant affects the same nucleotide/amino acid (c.1228G>A (p.Gly410Ser), providing moderate evidence for pathogenicity. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246180 control chromosomes. c.1228G>C has been reported in the literature in individuals affected with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner_2000, Donoghue_2018), including a patient reported as compound heterozygote with a known pathogenic variant. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
DHCR7-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 01, 2023 | The DHCR7 c.1228G>C variant is predicted to result in the amino acid substitution p.Gly410Arg. This variant was reported in compound heterozygosity in one patient with clinical and biochemical features consistent with Smith-Lemli-Opitz syndrome (Patient 13, Donoghue SE et al 2018. PubMed ID: 29455191). At least another patient with Smith-Lemli-Optiz syndrome has been reported with this variant. However, it is unclear if this patient was compound heterozygous for another DHCR7 variant. This variant is located in the transmembrane domain, where a large number of missense have been reported (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299). Another pathogenic substitution affecting this residue has also been reported in the literature (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299, Fitzky et al. 1998. PubMed ID: 9653161). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-71146621-C-G). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at