chr11-71441392-G-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001360.3(DHCR7):βc.461C>Gβ(p.Thr154Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000336 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 (β β ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T154M) 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.461C>G | p.Thr154Arg | missense_variant | 6/9 | ENST00000355527.8 | |
DHCR7 | NM_001163817.2 | c.461C>G | p.Thr154Arg | missense_variant | 6/9 | ||
DHCR7 | XM_011544777.3 | c.461C>G | p.Thr154Arg | missense_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.461C>G | p.Thr154Arg | missense_variant | 6/9 | 1 | NM_001360.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152232Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000961 AC: 24AN: 249850Hom.: 0 AF XY: 0.0000961 AC XY: 13AN XY: 135238
GnomAD4 exome AF: 0.000358 AC: 524AN: 1461718Hom.: 0 Cov.: 34 AF XY: 0.000329 AC XY: 239AN XY: 727164
GnomAD4 genome AF: 0.000125 AC: 19AN: 152232Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74378
ClinVar
Submissions by phenotype
Smith-Lemli-Opitz syndrome Pathogenic:10
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 26, 2021 | Variant summary: DHCR7 c.461C>G (p.Thr154Arg) results in a non-conservative amino acid change located in the membrane-associated helix (MAH 3, Waterham_2012) of 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-05 in 774648 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (4e-05 vs 0.0043), allowing no conclusion about variant significance. c.461C>G has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner_2001, Correa-Cerro__2005, Scalco_2005, Haas_2007, Boland_2016). These data indicate that the variant is very likely to be associated with disease. Additionally, another variant at the same residue T154M has been observed in affected SLOS individuals (Witsch-Baumgartner_2001, Correa-Cerro__2005, Boland_2016), suggesting that the variant is clinically significant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2) and likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 12, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 21, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 154 of the DHCR7 protein (p.Thr154Arg). This variant is present in population databases (rs143312232, gnomAD 0.02%). This missense change has been observed in individual(s) with DHCR7-related conditions (PMID: 15805162, 15952211, 17237122, 20694756). 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: 166988). 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.Thr154 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10677299, 10995508, 11427181, 15896653, 18249054, 22391996). 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, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 21, 2021 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Feb 24, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 09, 2021 | - - |
Likely pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Apr 27, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 16, 2018 | The DHCR7 c.461C>G (p.Thr154Arg) missense variant has been reported in at least four studies in which it is found in a total of four patients with either diagnosed or suspected Smith-Lemli-Opitz syndrome. The variant was present in three patients in a compound heterozygous state and in one patient in a heterozygous state, in whom it is not clear if a second variant was present (Witsch-Baumgartner et al. 2001; Correa-Cerro et al. 2005; Scalco et al. 2005; Haas et al. 2007). The p.Thr154Arg variant was also identified in a heterozygous state in six unaffected individuals in a large cohort undergoing routine carrier screening using next generation sequencing (Lazarin et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Thr154Arg variant is classified as likely pathogenic for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 12, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 05, 2022 | 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: 20694756, 10995508, 10677299, 29300326, 28166604, 23042628, 15805162, 11175299, 11241839, 15670717, 12914579, 17237122, 15952211, 34426522) - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 13, 2021 | The c.461C>G (p.T154R) alteration is located in exon 6 (coding exon 4) of the DHCR7 gene. This alteration results from a C to G substitution at nucleotide position 461, causing the threonine (T) at amino acid position 154 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD) database, the DHCR7 c.461C>G alteration was observed in 0.01% (25/281248) of total alleles studied, with a frequency of 0.02% (22/127708) in the European (non-Finnish) subpopulation. This mutation has been detected in four individuals with Smith-Lemli-Opitz syndrome (SLOS); three of the individuals carried another pathogenic mutation although the phase of these alterations was unknown (Witsch-Baumgartner, 2001; Correa-Cerro, 2005; Scalco, 2005; Haas, 2007). Based on our internal structural analysis, this mutation is predicted to be more destabilizing than nearby known pathogenic variants (Li, 2015). The p.T154R alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
DHCR7-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 13, 2023 | The DHCR7 c.461C>G variant is predicted to result in the amino acid substitution p.Thr154Arg. This variant has been reported in at least three patients with Smith-Lemli-Opitz syndrome (SLOS) in addition to a second known pathogenic DHCR7 variant (Correa-Cerro et al. 2005. PubMed ID: 15805162; Scalco et al. 2005. PubMed ID: 15952211; Haas et al. 2007. PubMed ID: 17237122). It has also been reported in other SLOS patient cohorts without additional genetic segregation data included about the reported patients (Witsch-Baumgartner et al. 2001. PubMed ID: 11241839; Witsch-Baumgartner et al. 2001. PubMed ID: 11175299). A different substitution of the same amino acid (p.Thr154Met) has been reported in a number of compound heterozygous SLOS patients (Wassif et al. 2005. PubMed ID: 15896653; Jezela-Stanek et al. 2008. PubMed ID: 18249054; Roullet et al. 2012. PubMed ID: 22391996) and in an expression study using HEK293 cells, the p.Thr154Met substitution was found to lead to <5% expression (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299). The p.Thr154 amino acid is located in the third membrane-associated helix (MAH 3) of the DHCR7 protein (Waterham and Hennekam. 2012. PubMed ID: 23042628), and an internal summary of amino acid substitution prediction programs predicts the p.Thr154Arg change to be βdamagingβ (Liu et al. 2016. PMID: 26555599). This variant has been reported at a frequency of ~0.015% in individuals of European (Non-Finnish) origin in a large population database and has been interpreted in ClinVar as pathogenic/likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/166988/). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at