The DHCR7 NM_001360.3:c.964-1G>C (NP_001351.2:p.?) splicing variant has previously been reported in somatic cancers (COSMIC; COSV106107975, n = 1 time). This variant is predicted to disrupt normal RNA processing, resulting in either an aberrant protein product or nonsense-mediated RNA decay. Experimental evidence: RT-PCR showed 134-base intron retention and frameshifting, while enzyme assays confirmed inactive DHCR7 in homozygous patients. Based on available guidelines, this variant is considered to be Pathogenic.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.DHCR7 encodes an enzyme in cholesterol production that converts 7-dehydrocholesterol into cholesterol in the endoplasmic reticulum. Changes in this gene cause Smith-Lemli-Opitz syndrome, a condition that can involve low cholesterol, developmental and intellectual disability, distinctive facial features, toe syndactyly, and, in severe cases, holoprosencephaly. DHCR7 has no established cancer role.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met (strong): canonical splice disruption causes a frameshift and inactive protein, but the premature stop lies in terminal exon 9 and is expected to escape NMD, requiring a one-tier downgrade.
Met, strong: RT-PCR showed 134-base intron retention and frameshifting, while enzyme assays confirmed inactive DHCR7 in homozygous patients.
Met: exact-variant case-control counts yield OR 155.75 (95% CI 19.17-1265.18), exceeding the PS4 threshold >5.0 with a confidence interval excluding 1.0.
Met at moderate strength: c.964-1G>C occurred in compound-heterozygous affected SLOS patients, including 8 compound heterozygotes among 13 patients in one study.
Met at moderate strength: SpliceAI max delta 0.992 exceeds the >=0.5 PP3 threshold for this intronic splice-site variant.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PVS1, PS3, and PS4 at strong strength, with PM3 and PP3 at moderate strength, satisfy the generic ACMG/AMP Pathogenic combination rules.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 11,914 / 1,599,960 alleles. Recorded AF 0.00744644. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.00385373; MAF= 0.38537%, 1010/262084 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0118223; MAF= 1.18223%, 116/9812 alleles, homozygotes = 0); grpmax FAF= 0.00571882.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.992. Refer to the recorded PP3/BP4 rationale for interpretation.
59 Pathogenic · 1 Likely pathogenic · 1 pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV106107975, n = 1 times).
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 5 met · 10 not met · 5 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PS4 is met because the exact variant is substantially enriched in SLOS probands versus controls: OR 155.75 with 95% CI 19.17-1265.18, satisfying OR >5.0 and excluding 1.0.
PP4 and BP5 are not assessed because the current-case phenotype/family-history and a qualifying alternate molecular diagnosis are not documented.
PP5 and BP6 are not met because the required exact-variant ClinVar expert-panel classifications are absent: zero expert-panel submissions are reported.
PM3 is met at moderate strength because the exact DHCR7 variant is documented in affected SLOS patients in compound-heterozygous configurations with different variants on the other allele.
BP2 is not met because the documented configurations are relevant to the recessive DHCR7 disorder and no qualifying cis observation or dominant-disorder trans observation is reported.
The variant is a canonical intronic splice-acceptor change; PP3 and BP4 were evaluated exclusively through SpliceAI, without using REVEL or BayesDel.
SpliceAI max delta 0.992 meets PP3 moderate but does not meet BP4 supporting.
No criteria match.
NM_001360.3:c.964-1G>C is a canonical -1 splice-acceptor variant in the disease-relevant DHCR7 transcript. Variant-specific RNA studies demonstrated activation of a cryptic splice site with retention of 134 intronic bases and a frameshift; the resulting transcript has a premature stop and produces a truncated DHCR7 protein lacking 154 C-terminal amino acids. Independent patient data report the same aberrant transcript and enzyme inactivity in homozygous individuals. DHCR7 loss of function is established as a disease mechanism in Smith-Lemli-Opitz syndrome. The affected exon is the terminal exon and contains the stop codon, so the premature stop is expected to escape nonsense-mediated decay; under the named PVS1 downgrade rule for an NMD-escaping truncation, the default very-strong call is downgraded one tier to strong. The terminal region is functionally important based on the observed inactive protein, so no additional non-critical-exon downgrade is applied.
PVS1: Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
PS3 is met at strong strength. The exact DHCR7 c.964-1G>C splice-acceptor variant was directly examined in variant-positive patient material. RT-PCR of fibroblast RNA demonstrated activation of a cryptic splice site with inclusion of 134 intronic bases and a frameshift (PMID:10814720). A separate study reported the same aberrant transcript, premature termination, and a truncated inactive DHCR7 protein, with loss of enzyme activity confirmed in patients homozygous for the variant (PMID:11427181). These are biologically relevant, variant-specific RNA and protein-function assays that directly demonstrate a damaging effect; no BS3-type normal-function result was identified.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Met at strong strength. PMID:10710236 directly reports the exact variant IVS8-1G>C (NM_001360.3:c.964-1G>C) in 21 of 33 SLOS probands and 1 of 90 unrelated US Caucasian controls. Treating these as a case-control comparison, the continuity-free 2x2 odds ratio is (21x89)/(12x1)=155.75; the Wald 95% CI is 19.17-1265.18, which excludes 1.0. The governing PS4 comparison is OR >5.0 and the confidence interval must not include 1.0: 155.75 > 5.0? yes; 19.17-1265.18 excludes 1.0? yes.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
DHCR7-related Smith-Lemli-Opitz syndrome is an autosomal recessive disorder. The exact variant NM_001360.3:c.964-1G>C (reported as IVS8-1G>C) was identified in affected SLOS patients in compound-heterozygous configurations with different DHCR7 variants. PMID:11427181 reports two homozygous patients and eight compound heterozygotes; its Table 2 identifies c.964-1G>C on one allele with a different missense variant on the other allele in multiple affected patients, and the Results/Discussion explicitly describes these as compound heterozygotes. This is direct affected-proband, trans-configuration evidence supporting the default PM3 moderate strength. PMID:10710236 independently reports the exact variant in 21 of 33 affected probands and documents parental segregation in five pedigrees, with the variant inherited from the father in three and the mother in two; it also states that the affected patients were compound heterozygotes for different mutations.
For recessive disorders, detected in trans with a pathogenic variant...This requires testing of parents (or offspring) to determine phase.
The variant is an intronic canonical splice-acceptor variant (NM_001360.3:c.964-1G>C), so the applicable PP3/BP4 path is SpliceAI only; REVEL is not used. SpliceAI max delta is 0.992 (DS_AL), which meets the generic PP3 moderate threshold of >= 0.5. The SpliceAI result supports a deleterious splice effect and is not combined with a REVEL or BayesDel prediction.
Intronic, synonymous, or splice-region variant -> SpliceAI only. There is no REVEL score to fall back to. ... PP3 (moderate): >= 0.5 — SpliceAI high-precision cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)
PS2 is not met. PMID:10710236 directly evaluated parental DNA in six pedigrees; the variant was present in five, with paternal origin in three and maternal origin in two. This is documented inheritance from a parent, not a de novo occurrence with confirmed maternity and paternity. No evidence in the reviewed material establishes a de novo event or the required absence of family history.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
PM2 is not met because the variant is present in population controls at a frequency far above the supplied PM2 supporting threshold of <=0.0001. Using the default all-comers source in the absence of a governing VCEP specification, gnomAD v4.1 reports AF=0.00744644 (11,914/1,599,960 alleles; 0 homozygotes), and gnomAD v2.1 reports AF=0.00385373 (1,010/262,084 alleles; 0 homozygotes). The variant was also observed heterozygously in 1 of 90 unrelated US Caucasian controls. These data are incompatible with absence or extremely low frequency in controls, even though no homozygotes were observed.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
PM6 is not met. PMID:10710236 reports parental testing in six pedigrees and identifies the variant as paternal in three and maternal in two of the five variant-positive pedigrees. The available evidence therefore supports documented parental inheritance, not an assumed de novo variant without parental confirmation.
Assumed de novo, but without confirmation of paternity and maternity.
Not met under the required generic PP5 gate. ClinVar reports the exact variant as Pathogenic/Likely pathogenic with multiple submitters, but the record has zero expert-panel submissions; the available assertions are laboratory submissions or aggregate labels, which cannot trigger PP5 here. The cited literature is independently available for evaluation and therefore does not satisfy the criterion's unavailable-evidence condition.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. No VCEP-specific population source applies, so the all-comers gnomAD data are used. The required filtering frequency is grpmax FAF, not the popmax point estimate: gnomAD v4.1 reports grpmax FAF=0.00906082 (0.906082%), based on 29,354 observed alleles, and gnomAD v2.1 reports grpmax FAF=0.00571882 (0.571882%), based on 9,812 observed alleles. Both are below the generic BA1 threshold of >=0.05 (5%). The Ashkenazi Jewish popmax point estimates of 1.21619% in v4.1 and 1.18223% in v2.1 do not establish BA1 because popmax is not the required filtering FAF.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met on the supplied generic threshold. No VCEP-specific population source applies, so the all-comers gnomAD data are used. The required filtering frequency is grpmax FAF: 0.00906082 (0.906082%) in gnomAD v4.1, with 29,354 observed alleles in the highest-frequency population, and 0.00571882 (0.571882%) in gnomAD v2.1, with 9,812 observed alleles. Both are below the generic BS1 default of >=0.01 (1%). The Ashkenazi Jewish popmax point estimates are not the required FAF. This is an autosomal-recessive disorder with a documented founder allele, so a population-specific maximum-credible-frequency calculation would be preferable to treating 1% as universal; however, it is unnecessary for this criterion because the validated grpmax FAF is already below 1%.
Allele frequency is greater than expected for disorder.
BS2 is not met. gnomAD v4.1 reports zero homozygotes among 1,599,960 observed alleles, and gnomAD v2.1 reports zero homozygotes among 262,084 observed alleles. The variant-specific literature describes affected individuals and carrier controls, not a healthy adult homozygote. Yu et al. observed the variant in 1 of 90 unrelated US Caucasian controls, but that observation was heterozygous and does not satisfy the recessive-disease BS2 requirement. No healthy adult homozygote is documented in the reviewed evidence.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
The governing BP2 definition applies to a pathogenic variant observed in trans with another pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern. The available DHCR7 observations are for Smith-Lemli-Opitz syndrome, an autosomal recessive disorder, and show the queried variant in affected individuals as homozygous or compound heterozygous; no qualifying cis observation was documented. Therefore the evidence does not satisfy BP2.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The variant is an intronic canonical splice-acceptor variant, so BP4 must be assessed using SpliceAI only; REVEL is not applicable to this consequence type. SpliceAI max delta is 0.992, which is above rather than at or below the generic BP4 supporting threshold of <= 0.1. Therefore the computational result does not support no splice impact, and BP4 is not met.
Intronic, synonymous, or splice-region variant -> SpliceAI only. There is no REVEL score to fall back to. ... BP4 (supporting): <= 0.1 — SpliceAI recommended cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)
Not met under the required generic BP6 gate. The exact variant has no ClinVar expert-panel benign or likely-benign classification; ClinVar instead reports Pathogenic/Likely pathogenic laboratory submissions and an aggregate pathogenic classification. Non-expert or laboratory assertions cannot trigger BP6 here.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
PP1 is not assessed. PMID:10710236 documents transmission of the variant from a father or mother to affected probands in five pedigrees, but it does not document co-segregation with disease in multiple affected family members. The available pedigree information is parental-origin evidence and is insufficient to apply PP1.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The rule requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The available evidence documents SLOS cohorts and the variant's occurrence in affected individuals, but does not provide the current patient's phenotype or family history in a form that permits a PP4 assessment.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS3 was not assessed because the available variant-specific functional studies evaluate abnormal splicing and loss of DHCR7 activity, not preserved protein function or normal splicing. No well-established assay result with appropriate normal-function controls showing that c.964-1G>C has no damaging effect was identified.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
BS4 is not assessed. The reviewed evidence does not identify affected family members who lack the variant. PMID:10710236 reports parental transmission in five pedigrees but does not provide a non-segregation analysis among affected relatives; therefore, lack of segregation cannot be established.
Lack of segregation in affected members of a family.
The rule requires the variant to be found in a case with an alternate molecular basis for disease. The available evidence does not establish an alternate molecular diagnosis in the current case or a qualifying BP5 case, so BP5 cannot be adjudicated.
Variant found in a case with an alternate molecular basis for disease.
PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_001360.3:c.964-1G>C in DHCR7 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001351.2:p.?. As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PS1 for DHCR7, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_001360.3:c.964-1G>C in DHCR7 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001351.2:p.?. As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM1 for DHCR7, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001360.3:c.964-1G>C in DHCR7 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001351.2:p.?. As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for DHCR7, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_001360.3:c.964-1G>C in DHCR7 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001351.2:p.?. As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM5 for DHCR7, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_001360.3:c.964-1G>C in DHCR7 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001351.2:p.?. As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PP2 for DHCR7, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_001360.3:c.964-1G>C in DHCR7 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001351.2:p.?. As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP1 for DHCR7, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001360.3:c.964-1G>C in DHCR7 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001351.2:p.?. As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for DHCR7, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001360.3:c.964-1G>C in DHCR7 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001351.2:p.?. As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for DHCR7, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in DHCR7, mapped onto the exon structure of NM_001360.3. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Ashkenazi Jewish357 / 29,354 | 0.012 |
| European (non-Finnish)10810 / 1,174,168 | 0.0092 |
| Remaining individuals409 / 62,012 | 0.0066 |
| Admixed American118 / 59,722 | 0.002 |
| European (Finnish)93 / 57,480 | 0.0016 |
| African/African American113 / 74,924 | 0.0015 |
| Middle Eastern2 / 6,038 | 0.00033 |
| South Asian12 / 90,726 | 0.00013 |
| Ashkenazi Jewish116 / 9,812 | 0.012 |
| European (non-Finnish)722 / 118,782 | 0.0061 |
| Remaining individuals31 / 6,836 | 0.0045 |
| Admixed American67 / 34,828 | 0.0019 |
| African/African American41 / 22,690 | 0.0018 |
| European (Finnish)30 / 19,724 | 0.0015 |
| South Asian3 / 30,116 | 0.0001 |
This variant is present in gnomAD v4.1 (AF= 0.00744644; MAF= 0.74464%, 11914/1599960 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0121619; MAF= 1.21619%, 357/29354 alleles, homozygotes = 0); grpmax FAF= 0.00906082.
This variant is present in gnomAD v2.1 (AF= 0.00385373; MAF= 0.38537%, 1010/262084 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0118223; MAF= 1.18223%, 116/9812 alleles, homozygotes = 0); grpmax FAF= 0.00571882.
Not available in gnomAD-Canada v1.0.
The variant is an intronic canonical splice-acceptor variant (NM_001360.3:c.964-1G>C), so the applicable PP3/BP4 path is SpliceAI only; REVEL is not used. SpliceAI max delta is 0.992 (DS_AL), which meets the generic PP3 moderate threshold of >= 0.5. The SpliceAI result supports a deleterious splice effect and is not combined with a REVEL or BayesDel prediction.
Intronic, synonymous, or splice-region variant -> SpliceAI only. There is no REVEL score to fall back to. ... PP3 (moderate): >= 0.5 — SpliceAI high-precision cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)
The variant is an intronic canonical splice-acceptor variant, so BP4 must be assessed using SpliceAI only; REVEL is not applicable to this consequence type. SpliceAI max delta is 0.992, which is above rather than at or below the generic BP4 supporting threshold of <= 0.1. Therefore the computational result does not support no splice impact, and BP4 is not met.
Intronic, synonymous, or splice-region variant -> SpliceAI only. There is no REVEL score to fall back to. ... BP4 (supporting): <= 0.1 — SpliceAI recommended cutoff (Jaganathan et al. 2019, Cell) (PMID:30661751)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001360.3:c.964-1G>C in DHCR7 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_001351.2:p.?. As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for DHCR7, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). REVEL score = 0.557. BayesDel score = 0.65.
12 paper records listed. 3 cited in the classification.
This results in abnormal splicing of the last exon, exon 9, with an insertion of a 134 bp insertion of intron 8 sequences, a resultant frame-shift with premature translational stop.
Location Introduction; Results and Discussion; Table I; Fig. 1
Context PCR amplification and sequencing of a 556-bp intron 8/exon 9 fragment, with AlwNI PCR-RFLP confirmation; 33 SLOS probands, six pedigrees with parental DNA, and population controls.
this mutation leads to activation of a cryptic splice site, resulting in the inclusion of 134 bases of intronic sequences and frame-shift
Location Results, Mutation detection; Table 1; Discussion
Context Mutation screening and sequencing in 32 SLOS patients, with RT-PCR analysis of fibroblast RNA from probands carrying the splice-site variant.
The IVS8−1 G " C mutation causes aberrant splicing, producing an mRNA with 134 base-pairs of retained intron 8 sequence at nucleotide position 963, which leads to a frame shift and a stop codon at nucleotide 1235 (TGA). This premature termination of translation results in a truncated and inactive DHCR7 protein, as was confirmed by enzyme activity measurements in the patients homozygous for this mutation.
Location Results, paragraph 3; Discussion, paragraph 2; Table 2; Conclusion
Context DHCR7 sequence analysis in 13 biochemically confirmed SLOS patients, including 26 SLOS alleles; enzyme activity measurements were performed in patients homozygous for the variant.
one splice-site mutation (IVS8-1GrC) resulting in a 134-bp insertion because of alternative splicing, and a nonsense mutation (W151X); all of these nonmissense mutations are predicted to result in truncated proteins and may also cause mRNA instability (Maquat 1996).
Results, Mutational Spectrum; Table 2; Table 3; Table 5; Discussion
By far the most prevalent mutation in Caucasians is the severe c.964-1G>C splice site mutation (allele frequency of ~30%),
Results, "DHCR7 Mutations in SLOS"; Table I; Table III
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.00744644; MAF= 0.74464%, 11914/1599960 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0121619; MAF= 1.21619%, 357/29354 alleles, homozygotes = 0); grpmax FAF= 0.00906082.
This variant is present in gnomAD v2.1 (AF= 0.00385373; MAF= 0.38537%, 1010/262084 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0118223; MAF= 1.18223%, 116/9812 alleles, homozygotes = 0); grpmax FAF= 0.00571882.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (59 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as pathogenic (1 clinical laboratory). (ClinVarID = 93725)
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). REVEL score = 0.557. BayesDel score = 0.65.
This variant has previously been reported in somatic cancers (COSMIC; COSV106107975, n = 1 times).