chr11-71441392-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_001360.3(DHCR7):c.461C>T(p.Thr154Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,613,950 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. T154R) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.461C>T | p.Thr154Met | missense_variant | 6/9 | ENST00000355527.8 | |
DHCR7 | NM_001163817.2 | c.461C>T | p.Thr154Met | missense_variant | 6/9 | ||
DHCR7 | XM_011544777.3 | c.461C>T | p.Thr154Met | missense_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.461C>T | p.Thr154Met | missense_variant | 6/9 | 1 | NM_001360.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152232Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249850Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135238
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461718Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10AN XY: 727164
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152232Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74378
ClinVar
Submissions by phenotype
Smith-Lemli-Opitz syndrome Pathogenic:7
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 | Sep 03, 2020 | Variant summary: DHCR7 c.461C>T (p.Thr154Met) 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 4e-06 in 249850 control chromosomes (gnomAD). c.461C>T has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Wassif_2005, Jira_2001, Krakowiak_2000, Witsch-Baumgartner_2000, Eroglu_2017). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated patients carrying the variant of interest along with other pathogenic variants to exhibit decreased fractional cholesterol synthesis and expression studies showed this variant results in reduced protein expression in cell line (Witsch-Baumgartner_DHCR7_AJHG_2000, Wassif_2005). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Aug 20, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 27, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 28, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 13, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 154 of the DHCR7 protein (p.Thr154Met). This variant is present in population databases (rs143312232, gnomAD 0.0009%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10677299, 10995508, 11427181, 15896653, 18249054, 22391996). ClinVar contains an entry for this variant (Variation ID: 188923). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at