NM_001360.3:c.1079T>C

Variant names:

• chr11-71435724-A-G
• rs1555145619
• NM_001360.3:c.1079T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.36
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Smith-Lemli-Opitz syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 [Pathogenic]. Clinvar id is 553336.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.1079T>C	p.Leu360Pro	missense_variant	Exon 9 of 9	ENST00000355527.8	NP_001351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.1079T>C	p.Leu360Pro	missense_variant	Exon 9 of 9	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.494T>C	p.Leu165Pro	missense_variant	Exon 8 of 8			ENSP00000509319.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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. 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). -

Aug 15, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

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
PhyloP100		6.4
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
Varity_R		0.92
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs1555145619; hg19: chr11-71146770;