chr11-71435397-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001360.3(DHCR7):ā€‹c.1406G>Cā€‹(p.Arg469Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,034 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

DHCR7
NM_001360.3 missense

Scores

11
7
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 5.22
Variant links:
Genes affected
DHCR7 (HGNC:2860): (7-dehydrocholesterol reductase) This gene encodes an enzyme that removes the C(7-8) double bond in the B ring of sterols and catalyzes the conversion of 7-dehydrocholesterol to cholesterol. This gene is ubiquitously expressed and its transmembrane protein localizes to the endoplasmic reticulum membrane and nuclear outer membrane. Mutations in this gene cause Smith-Lemli-Opitz syndrome (SLOS); a syndrome that is metabolically characterized by reduced serum cholesterol levels and elevated serum 7-dehydrocholesterol levels and phenotypically characterized by cognitive disability, facial dysmorphism, syndactyly of second and third toes, and holoprosencephaly in severe cases to minimal physical abnormalities and near-normal intelligence in mild cases. Alternative splicing results in multiple transcript variants that encode the same protein.[provided by RefSeq, Aug 2009]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
Variant 11-71435397-C-G is Pathogenic according to our data. Variant chr11-71435397-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449476.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}. Variant chr11-71435397-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DHCR7NM_001360.3 linkuse as main transcriptc.1406G>C p.Arg469Pro missense_variant 9/9 ENST00000355527.8 NP_001351.2 Q9UBM7A0A024R5F7
DHCR7NM_001163817.2 linkuse as main transcriptc.1406G>C p.Arg469Pro missense_variant 9/9 NP_001157289.1 Q9UBM7A0A024R5F7
DHCR7XM_011544777.3 linkuse as main transcriptc.*169G>C 3_prime_UTR_variant 9/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DHCR7ENST00000355527.8 linkuse as main transcriptc.1406G>C p.Arg469Pro missense_variant 9/91 NM_001360.3 ENSP00000347717.4 Q9UBM7
DHCR7ENST00000685320.1 linkuse as main transcriptc.821G>C p.Arg274Pro missense_variant 8/8 ENSP00000509319.1 B4E1K5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1460034
Hom.:
0
Cov.:
30
AF XY:
0.00000551
AC XY:
4
AN XY:
726406
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00000526
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:1Uncertain:2
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 25, 2023This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 469 of the DHCR7 protein (p.Arg469Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10814720). ClinVar contains an entry for this variant (Variation ID: 449476). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Jan 20, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingCounsylOct 25, 2017- -
DHCR7-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 07, 2023The DHCR7 c.1406G>C variant is predicted to result in the amino acid substitution p.Arg469Pro. This variant has been reported in the compound heterozygous state in an individual with Smith-Lemli-Opitz syndrome (Yu et al. 2000. PubMed ID: 10814720). This variant was also reported in the heterozygous state in an additional affected individual in the same study, however, a second potentially pathogenic allele was not identified (Yu et al. 2000. PubMed ID: 10814720). This variant has also been reported as in an exome cohort study and interpreted as likely pathogenic (Supplemental File 1 - Rego et al. 2018. PubMed ID: 30487145). Furthermore, alternate missense variants affecting the same amino acid (p.Arg469Cys, p.Arg469His) have also been reported to be associated with Smith-Lemli-Opitz syndrome (Cross et al. 2015. PubMed ID: 24813812). This variant is interpreted as likely pathogenic. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 03, 2017The R469P variant in the DHCR7 gene has been reported previously in a female patient with Smith-Lemli-Opitz syndrome (SLOS) who also harbored the E448K variant in unknown phase, and in a male patient with SLOS who had no second variant identified (Yu et al., 2000). The R469P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R469P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (V466M, V466A, P467L, L470Q) have been reported in the Human Gene Mutation Database in association with SLOS (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R469P as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D;D
Eigen
Pathogenic
0.77
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.95
.;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.0
H;H
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-5.7
D;D
REVEL
Pathogenic
0.94
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.0060
D;D
Polyphen
1.0
D;D
Vest4
0.90
MutPred
0.86
Loss of methylation at R469 (P = 0.0355);Loss of methylation at R469 (P = 0.0355);
MVP
0.98
MPC
0.68
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.98
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201150384; hg19: chr11-71146443; API