rs1046560765
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001360.3(DHCR7):āc.1222T>Cā(p.Tyr408His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,611,300 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. Y408F) 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.1222T>C | p.Tyr408His | missense_variant | 9/9 | ENST00000355527.8 | |
DHCR7 | NM_001163817.2 | c.1222T>C | p.Tyr408His | missense_variant | 9/9 | ||
DHCR7 | XM_011544777.3 | c.1356T>C | p.Thr452= | synonymous_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.1222T>C | p.Tyr408His | missense_variant | 9/9 | 1 | NM_001360.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 35
GnomAD3 exomes AF: 0.00000405 AC: 1AN: 246792Hom.: 0 AF XY: 0.00000744 AC XY: 1AN XY: 134360
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1459086Hom.: 0 Cov.: 85 AF XY: 0.00 AC XY: 0AN XY: 725996
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 74366
ClinVar
Submissions by phenotype
Smith-Lemli-Opitz syndrome Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 23, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 31, 2022 | This variant is present in population databases (no rsID available, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 552616). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10677299, 10995508, 12818773, 15896653). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 408 of the DHCR7 protein (p.Tyr408His). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 06, 2023 | Variant summary: DHCR7 c.1222T>C (p.Tyr408His) results in a conservative amino acid change located in the 4th Cytoplasmic loop/TM domain (Witsch-Baumgartner_2000) of 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 4.1e-06 in 246792 control chromosomes. c.1222T>C has been reported in the literature as a compound heterozygous genotype in individuals affected with Smith-Lemli-Opitz Syndrome (example, PMID: 10995508, 23918729, 22438180, 33890232, 15896653, 15954111, 10677299). 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. Two 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 09, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed multiple times with a second DHCR7 variant in unrelated patients with Smithh-Lemli-Opitz syndrome in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Krakowiak et al., 2000; Waye et al., 2005; Lee et al., 2013); This variant is associated with the following publications: (PMID: 11942534, 12818773, 28166604, 34308104, 11767235, 11001806, 15954111, 22438180, 23042628, 10995508, 10677299, 23918729, 12914579, 11111101, 33890232, 18076100, 15896653) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at