rs1317526744

Positions:

• chr11-71435781-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001360.3(DHCR7):​c.1022T>C​(p.Leu341Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 1,456,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 8.12

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 4 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity DHCR7_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_001360.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.1022T>C	p.Leu341Pro	missense_variant	9/9	ENST00000355527.8	NP_001351.2
DHCR7	NM_001163817.2	c.1022T>C	p.Leu341Pro	missense_variant	9/9		NP_001157289.1
DHCR7	XM_011544777.3	c.1156T>C	p.Cys386Arg	missense_variant	9/9		XP_011543079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.1022T>C	p.Leu341Pro	missense_variant	9/9	1	NM_001360.3	ENSP00000347717	P1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247380 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134564

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000892 AC: 13 AN: 1456786 Hom.: 0 Cov.: 37 AF XY: 0.0000111 AC XY: 8 AN XY: 723910

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 19, 2021	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. 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. This variant has been observed in individual(s) with DHCR7-related conditions (PMID: 10995508). ClinVar contains an entry for this variant (Variation ID: 551380). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 341 of the DHCR7 protein (p.Leu341Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 05, 2017	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2020

The p.L341P variant (also known as c.1022T>C), located in coding exon 7 of the DHCR7 gene, results from a T to C substitution at nucleotide position 1022. The leucine at codon 341 is replaced by proline, an amino acid with similar properties. This variant was detected in an individual with Smith-Lemli-Opitz syndrome in conjunction with a second variant; however, phase was not confirmed (Krakowiak PA et al. Am. J. Med. Genet., 2000 Sep;94:214-27). Analysis in cells from this individual demonstrated reduced fractional cholesterol synthesis compared to wild type (Wassif CA et al. Mol. Genet. Metab., 2005 Jun;85:96-107). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10995508) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Benign	0.92
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.16	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	1.6	N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
MutPred		0.33		Gain of MoRF binding (P = 0.0108);
MVP		0.88
ClinPred		0.97	D
GERP RS		5.1

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: rs1317526744; hg19: chr11-71146827;