11-71435397-C-G

Position:

• chr11-71435397-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001360.3(DHCR7):​c.1406G>C​(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 𝑓: 0.0000034 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 5.22

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]

DHCR7 (HGNC:):

ACMG classification

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
DHCR7	NM_001360.3	c.1406G>C	p.Arg469Pro	missense_variant	9/9	ENST00000355527.8	NP_001351.2
DHCR7	NM_001163817.2	c.1406G>C	p.Arg469Pro	missense_variant	9/9		NP_001157289.1
DHCR7	XM_011544777.3	c.*169G>C		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.1406G>C	p.Arg469Pro	missense_variant	9/9	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.821G>C	p.Arg274Pro	missense_variant	8/8			ENSP00000509319.1

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

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:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:1 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2023	This 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 provided	clinical testing	Natera, Inc.	Jan 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 25, 2017	- -

DHCR7-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2023

The 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 submitter

clinical testing

GeneDx

Jul 03, 2017

The 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

Other links and lift over

dbSNP: rs201150384; hg19: chr11-71146443;