chr11-71435840-C-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001360.3(DHCR7):c.964-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00745 in 1,599,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001360.3 splice_acceptor, intron
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 rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DHCR7 | NM_001360.3 | c.964-1G>C | splice_acceptor_variant, intron_variant | Intron 8 of 8 | ENST00000355527.8 | NP_001351.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DHCR7 | ENST00000355527.8 | c.964-1G>C | splice_acceptor_variant, intron_variant | Intron 8 of 8 | 1 | NM_001360.3 | ENSP00000347717.4 | |||
| DHCR7 | ENST00000685320.1 | c.379-1G>C | splice_acceptor_variant, intron_variant | Intron 7 of 7 | ENSP00000509319.1 |
Frequencies
GnomAD3 genomes 0.00425 AC: 647AN: 152210Hom.: 0 Cov.: 35
GnomAD3 exomes AF: 0.00386 AC: 890AN: 230702Hom.: 0 AF XY: 0.00392 AC XY: 500AN XY: 127518
GnomAD4 exome AF: 0.00778 AC: 11267AN: 1447632Hom.: 0 Cov.: 36 AF XY: 0.00740 AC XY: 5318AN XY: 718890
GnomAD4 genome 0.00425 AC: 647AN: 152328Hom.: 0 Cov.: 35 AF XY: 0.00365 AC XY: 272AN XY: 74476
ClinVar
Submissions by phenotype
Smith-Lemli-Opitz syndrome Pathogenic:36Other:2
The DHCR7 c.964-1G>C variant (rs138659167) is reported in the literature as the most common variant in individuals affected with Smith-Lemli-Opitz (SLO) syndrome (reviewed in Witsch-Baumgartner 2015), found in both the homozygous and compound heterozygous state (Fitzky 1998, Krakowiak 2000, Witsch-Baumgartner 2000). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 93725), and is found in the general population with an overall allele frequency of 0.39% (1,010/262,084 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice acceptor site of intron 8, which is likely to disrupt gene function. Functional studies from patient mRNA show an insertion of 134 nucleotides between exons 8 and 9, leading to a premature termination codon (Fitzky 1998). Based on available information, the c.964-1G>C variant is considered to be pathogenic. References: Fitzky BU et al. Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8181-6. Krakowiak PA et al. Mutation analysis and description of sixteen RSH/Smith-Lemli-Opitz syndrome patients: polymerase chain reaction-based assays to simplify genotyping. Am J Med Genet. 2000 94(3):214-27. Witsch-Baumgartner M et al. Mutational spectrum in the Delta7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome. Am J Hum Genet. 2000 66(2):402-12. Witsch-Baumgartner M and Lanthaler B. et al. Birthday of a syndrome: 50 years anniversary of Smith-Lemli-Opitz Syndrome. Eur J Hum Genet. 2015 Mar;23(3):277-8. -
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ACMG codes: PVS1, PS3, PM2, PP5 -
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Variant interpretted as Pathogenic and reported on 06-04-2019 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
The DHCR7 c.964-1G>C variant is located at the splice acceptor site in intron 8 and has been shown to cause aberrant mRNA splicing and insertion of 134bp of intron DNA sequence resulting in a frameshift that prematurely truncates the protein (PMID: 9653161) (PVS1). The variant is the most common pathogenic variant in the DHCR7 gene (approx 29% of SLOS alleles), and has been reported in multiple patients with autosomal recessive Smith-Lemli-Opitz syndrome (SLOS) in both the homozygous or compound heterozygous state (PMID: 24824134, 23042628, 10814720, 10995508, 11427181 and ClinVar ID:93725) (PS4). The variant is in gnomAD (647/152,210 heterozygotes, 0 homozygotes ). The variant has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 93725) and has been reported in the HGMD database: CS982160. -
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The c.964-1G>C variant in DHCR7 has been reported in >50 patients with Smith-Lemli-Opitz syndrome (SLO) who were either homozygous or compound heterozygous for this variant (Fitzky 1998 PMID: 9653161, Krakowiak 2000 PMID: 10995508, Witsch-Baumgartner 2000 PMID: 10677299). It is one of the most common variants reported in patients with this disorder. This variant has also been reported in ClinVar (Variation ID 93725) and identified in 1.3% (44/3472) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), which is consistent with the carrier frequency for SLO. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence in the last intron/exon junction and is predicted to cause altered splicing leading to an abnormal protein. Functional studies using RT-PCR of patient mRNA isolated from fibroblasts show that that this variant leads to the use of an alternative splice acceptor in intron 8, which results in the insertion of 134 bp of intronic sequence, and ultimately a frameshift and premature termination with >10% of the protein affected (Fitzky 1998 PMID: 9653161). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive SLO syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PM3_VeryStrong. -
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Criteria applied: PM3_VSTR,PVS1_STR -
The c.964-1G>C variant is located in a canonical splice-site, and it is not predicted the protein reading frame alteration, however, occur in a critical region and the variant disrupts <10% of protein - PVS1_moderate. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 15805162) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 93725, PMID: 22226660; 22211794; 23042628) - PS4. The c.964-1G>C was detected in trans with a pathogenic variant (PMID: 22226660) - PM3 and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic. -
This sequence change affects an acceptor splice site in intron 8 of the DHCR7 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs138659167, gnomAD 1.2%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10814720, 10995508, 11427181, 23042628). 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: 93725). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a new termination codon (PMID: 9653161). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
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The c.964-1G>C splice variant in the DHCR7 gene has been previously reported in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner et al., 2000; Jira et al., 2001; Fitzky et al., 1998; Krakowiak et al., 2000). In one individual, this variant was observed in trans with a known pathogenic variant, p.Pro51Leu (Fitzky et al., 1998). Furthermore, RT-PCR and sequencing of the variant transcript showed that this variant leads to the use of an alternative splice acceptor in intron 8, which results in the insertion of 134 bp of intronic sequence, and ultimately a frameshift and premature termination (Fitzky et al., 1998). Loss of function is a mechanism of disease for this condition, however, no pathogenic nonsense or splice variants have been reported in DHCR7 downstream of this variant. This variant is reported at significantly higher frequency in affected individuals than the general population (OR=108.9000 (14.51-817.55)) (Witsch-Baumgartner et al., 2000). Multiple in silico algorithms predict this variant to be conserved and deleterious (CADD = 19.68; GERP=5.08). Emory Genetics Laboratory has classified this variant as Pathogenic, and The Genetic Services Laboratory of the University of Chicago has classified it as Likely Pathogenic. DHCR7 is the only gene in which variants have been shown to cause Smith-Lemli-Opitz Syndrome. Therefore, this collective evidence supports the classification of the c.964-1G>C as a Pathogenic variant for Smith-Lemli-Opitz Syndrome. We have confirmed this finding in our laboratory using Sanger sequencing. -
This sequence variant is a single nucleotide substitution (G>C) at the -1 position of the canonical splice acceptor site upstream of exon 9 of the DHCR7 gene. This is a previously reported variant (ClinVar 93725) that is a known pathogenic founder variant and the most common variant associated with recessive Smith-Lemli-Opitz syndrome (PMID: 10677299, 9683613, 23042628, 28166604, 32055014); it is also previously known as IVS8?1G>C. This variant is present in 11914 of 1599960 alleles (0.7446%) in the gnomAD population dataset. Splicing studies demonstrate that this variant causes alternative splicing which incorporates a frameshifting 134-bp insertion in the mRNA transcript (PMID: 10677299, 9683613). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM3, PS3, PS4, PVS1 -
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NG_012655.2(NM_001360.2):c.964-1G>C in the DHCR7 gene has an allele frequency of 0.012 in Ashkenazi Jewish subpopulation in the gnomAD database. The c.964-1G>C (IVS8-1G>C) is the most common pathogenic variant for Smith-Lemli-Opitz syndrome accounting for at least 29% of all disease alleles (PMID: 24824134). Functional analysis of the variant using RT-PCR in patient with skin fibroblasts demonstrated that the variant causes aberrant mRNA splicing and insertion of 134 bp resulting in a frameshift that prematurely truncates the protein. The insertion occurs in a region strongly conserved among sterol reductases (PMID: 9683613). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PS4; PS3. -
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The DHCR7 c.964-1G>C variant has been reported as one of the most common variants in affected individuals with Smith-Lemli-Opitz syndrome (Sanghera AS and Zeppieri M, PMID: 38261705). It is observed in the compound heterozygous (Fitzky BU et al., PMID: 9653161; Quelin C et al., PMID: 22226660) and homozygous states in multiple individuals (Quelin C et al., PMID: 22226660). This variant occurs within the canonical splice acceptor site, which is predicted to cause skipping of the exon, leading to an in-frame transcript that disrupts less than 10% of the protein. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 1.18% in the Ashkenazi Jewish population. This variant has been reported in the ClinVar database as a germline pathogenic variant by 10 submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -
PVS1, PM3_strong -
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DHCR7 c.964-1G>C is believed to be the most common disease-causing variant associated with Smith-Lemli-Opitz (SLO) syndrome and has been identified in affected individuals in both the homozygous and heterouzygous state. Five submitters in ClinVar classify this variant as either pathogenic or likely pathogenic. This DHCR7 variant (rs138659167) is present in a large population dataset (gnomAD: 1010/262084 total alleles; 0.3854%; no homozygotes) at a frequency that is consistent with the carrier frequency for SLO. We consider this variant to be pathogenic. -
NM_001360.2(DHCR7):c.964-1G>C is classified as pathogenic in the context of Smith-Lemli-Opitz syndrome and is associated with the severe form of the disease. Sources cited for classification include the following: PMID 15952211 and 10677299. Classification of NM_001360.2(DHCR7):c.964-1G>C is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
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The inherited c.964-1G>C splice site variant identified in the DHCR7 gene is a known pathogenic variant and is the most common variant detected in individuals affected with SLOS (found in approximately 30% of patients). It has been reported in the literature in both the homozygous and compound heterozygous state [PMID: 23042628, 24824134]. This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 93725). The varian thas .004251 allele frequency in the gnomAD(v3) database (647 out of 152210 heterozygous alleles, no homozygotes). The variant affects the canonical splice acceptor site in intron 8 (the last intron, transcript NM_001360.2) of DHRC7 gene. In vitro functional studies showed that the variant causes aberrant mRNA splicing resulting in insertion of 134 nucleotides which alters the wild type translational reading frame and introduces a premature translation termination codon [PMID: 9653161]. Based on the available evidence, the inherited c.964-1G>C splice site variant is reported as Pathogenic. -
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -
known pathogenic variant: PMID 28805615, 22226660, 28369852, 12818773, 12914579, 29455191, 22929031 and others. -
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) 0115 - Variants in this gene are known to have variable expressivity. Exceptionally mild and severe cases have been reported, with intrafamilial and interfamilial variable expressivity (PMID: 35305950, GeneReviews). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RNA studies have shown this variant results in a truncated protein with less than 1/3 of the protein affected (PMID: 9653161). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1010 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site has been observed in gnomAD (v2: 17 heterozygotes, 0 homozygotes). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been detected in multiple unrelated individuals with Smith-Lemli-Opitz syndrome, both homozygous and compound heterozygous (ClinVar, PMIDs: 9653161, 29455191) and is recognised as the most common pathogenic variant in this gene (GeneReviews). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). The proband of this family has been analysed by an external laboratory. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
The DHCR7 c.964-1G>C variant results in a substitution at the consensus splice acceptor site, which may result in splicing defects. The variant is well described in the literature and is the most common pathogenic variant for Smith-Lemli-Opitz syndrome accounting for at least 29% of all disease alleles (PMID: 24824134). Across a selection of the available literature, the c.964-1G>C variant has been identified in over 80 patients, including at least 32 in a homozygous state and 49 in a compound heterozygous state (PMID: 9683613; 9653161; 10995508; 10814720; 11427181; 23293579; 32055014; 33204589). Individuals who are homozygous for the variant manifest a severe phenotype while compound heterozygotes have a more variable phenotype ranging from mild to severe (PMID: 32055014; 33204589). The highest frequency of this allele in the Genome Aggregation Database is 0.01182 in the Ashkenazi Jewish population (version 2.1.1). This frequency is high but is consistent with disease prevalence estimates. Functional analysis of the variant using RT-PCR in patient skin fibroblasts demonstrated that the variant causes aberrant mRNA splicing and insertion of 134 bp between exons 8 and 9 resulting in a frameshift that prematurely truncates the protein. The insertion occurs in a region strongly conserved among sterol reductases (PMID: 9683613). Based on the available evidence, the c.964-1G>C variant is classified as pathogenic for Smith-Lemli-Opitz syndrome. -
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not provided Pathogenic:13
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DHCR7: PVS1, PM2, PM3, PP4 -
The DHCR7 c.964-1G>C variant has been reported in over 70 cases of autosomal recessive Smith Lemli Opitz syndrome (SLOS) and is the most common variant known to cause the disorder, accounting for ~28% of disease alleles (Nowaczyk_1998_PMID:20301322; Fitzky_1998_PMID:9653161; Krakowiak_2000_PMID:10995508; Witsch-Baumgartner_2001_PMID:11175299; DeBarber_2011_PMID:21777499). The variant was identified in dbSNP (ID: rs138659167) and ClinVar (classified as pathogenic by Laboratory for Molecular Medicine, Invitae and 21 other laboratories, and as likely pathogenic by Genetic Services Laboratory, University of Chicago and Equipe Genetique des Anomalies du Developpement, Université de Bourgogne). The variant was identified in control databases in 1010 of 262084 chromosomes (0 homozygous) at a frequency of 0.003854 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 116 of 9812 chromosomes (freq: 0.01182), European (non-Finnish) in 722 of 118782 chromosomes (freq: 0.006078), Other in 31 of 6836 chromosomes (freq: 0.004535), Latino in 67 of 34828 chromosomes (freq: 0.001924), African in 41 of 22690 chromosomes (freq: 0.001807), European (Finnish) in 30 of 19724 chromosomes (freq: 0.001521) and South Asian in 3 of 30116 chromosomes (freq: 0.0001), but was not observed in the East Asian population. The c.964-1G>C variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict the loss of the canonical 3' splice site. Functional analysis has confirmed this aberrant splicing prediction and has revealed the use of an alternative splice acceptor site that produces a shifted reading frame and premature stop codon (Fitzky_1998_PMID:965316). Another functional study suggests that the c.964-1G>C variant disrupts SMO cilia localization and SHH pathway activation due to reduced cholesterol biosynthesis and reduced levels of the DHCR7 transcript (Blassberg_2016_PMID:26685159). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
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Considered to be the most common pathogenic variant associated with Smith-Lemli-Opitz syndrome among individuals from North America and Western Europe (PMID: 9653161, 21777499); RT-PCR and RNA analysis revealed c.964-1 G>C leads to the use of an alternative splice acceptor site upstream of the native intron 8 splice site, which results in insertion of intronic sequence, a shift in reading frame, and a premature stop of translation (PMID: 9653161, 37301908); This variant is associated with the following publications: (PMID: 22975760, 20556518, 25405082, 17965227, 25108116, 27065010, 28250423, 36064943, 36035117, 26685159, 11857552, 9634533, 34930662, 30586318, 33879512, 21777499, 9653161, 33249554, 37323201, 37589029, 12949967, 28369852, 25533962, 28805615, 30609409, 29455191, 11298379, 30947698, 30925529, 31395954, 32257592, 31974414, 31618753, 32304219, 32055014, 31980526, 34426522, 31589614, 32058062, 33204589, 33578785, 32746448, 31785789, 23293579, 35506549, 34308104, 31847883, 37301908, 10995508) -
This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org); however DHC7 c.964-1G>C is reported to account for 1/3rd of all pathogenic alleles and described as a founder variant (PMID:11175299,17965227,16906538). Assessment of experimental evidence suggests this variant results in abnormal protein function. RT-PCR study showed that disruption of this splice site led to a premature stop codon (PMID:9653161). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
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PS4, PVS1_strong -
See cases Pathogenic:2
ACMG classification criteria: PVS1, PS3, PS4, PM3 -
ACMG categories: PVS1,PM1,PM2,BS1 -
Inborn genetic diseases Pathogenic:1
The c.964-1G>C intronic variant results from a G to C substitution one nucleotide before exon 9 (coding exon 7) of the DHCR7 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the C allele has an overall frequency of 0.385% (1010/262084) total alleles studied. The highest observed frequency was 1.182% (116/9812) of Ashkenazi Jewish alleles. This alteration is one of the most common DHCR7 mutations in North America and Western Europe, and was found to account for 35% of mutations in a cohort of 263 individuals with Smith-Lemli-Optiz syndrome (SLOS) (Witsch-Baumgartner, 2008). This mutation was reported in the homozygous state in a fetus with holoprosencephaly and multiple congenital anomalies as well as in newborns with a severe phenotype (Nowaczyk, 2001). This nucleotide position is highly conserved in available vertebrate species. Analysis of cDNA isolated from fibroblasts of a compound heterozygous individual with this alteration demonstrated the use of an alternative splice acceptor site, leading to a transcript with a shift in reading frame and a premature stop codon (Fitzky, 1998). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. -
DHCR7-related disorder Pathogenic:1
The DHCR7 c.964-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This canonical splice variant, often referred to in earlier literature as IVS8-1G>C, has been documented as causative for Smith-Lemli-Opitz syndrome (SLOS) (Fitzky et al. 1998. PubMed ID: 9653161; Witsch-Baumgartner et al. 2000. PubMed ID: 10677299). RT-PCR studies have shown that the c.964-1G>C variant results in the use of an alternative splice acceptor site, resulting in the insertion of 134 bp of intronic DNA sequence and subsequent premature termination (Fitzky et al. 1998. PubMed ID: 9653161). This variant has been reported in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/93725/) and is reported in 1.2% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at