rs1555145619

chr11-71435724-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_001360.3(DHCR7):c.1079T>C(p.Leu360Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.36

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_001360.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-71435724-A-G is Pathogenic according to our data. Variant chr11-71435724-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553336.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}. Variant chr11-71435724-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHCR7	NM_001360.3	c.1079T>C	p.Leu360Pro	missense_variant	9/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.1079T>C	p.Leu360Pro	missense_variant	9/9
DHCR7	XM_011544777.3	c.1213T>C	p.Cys405Arg	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.1079T>C	p.Leu360Pro	missense_variant	9/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 19, 2023	This missense change has been observed in individual(s) with Smith–Lemli–Opitz syndrome (PMID: 15521979). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 553336). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 360 of the DHCR7 protein (p.Leu360Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	29
Dann	Benign	0.91
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.17	T
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	1.7	N
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
MutPred		0.30		Gain of methylation at C194 (P = 0.041);
MVP		0.86
ClinPred		0.95	D
GERP RS		4.0

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: rs1555145619; hg19: chr11-71146770;