NM_001360.3:c.278C>A

Variant names:

• chr11-71444036-G-T
• rs80338853
• NM_001360.3:c.278C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The NM_001360.3(DHCR7):​c.278C>A​(p.Thr93Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T93M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.93
• Publications: 0 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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-71444036-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818
• PP5: Variant 11-71444036-G-T is Pathogenic according to our data. Variant chr11-71444036-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2968929.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001360.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	NM_001360.3	MANE Select	c.278C>A	p.Thr93Lys	missense	Exon 4 of 9	NP_001351.2
	DHCR7	NM_001425107.1		c.278C>A	p.Thr93Lys	missense	Exon 4 of 10	NP_001412036.1
	DHCR7	NM_001425108.1		c.278C>A	p.Thr93Lys	missense	Exon 4 of 9	NP_001412037.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.278C>A	p.Thr93Lys	missense	Exon 4 of 9	ENSP00000347717.4
	DHCR7	ENST00000407721.6	TSL:1	c.278C>A	p.Thr93Lys	missense	Exon 4 of 9	ENSP00000384739.2
	DHCR7	ENST00000685320.1		c.-308C>A		5_prime_UTR	Exon 3 of 8	ENSP00000509319.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:1

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant disrupts the p.Thr93 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9653161, 10602371, 10995508, 14981719). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 not been reported in the literature in individuals affected with DHCR7-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 93 of the DHCR7 protein (p.Thr93Lys).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.97	D
Eigen	Benign	-0.072
Eigen_PC	Benign	-0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.9
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.68
Sift	Benign	0.082	T
Sift4G	Benign	0.17	T
Polyphen		0.85	P
Vest4		0.53
MutPred		0.56		Gain of methylation at T93 (P = 0.007)
MVP		0.92
MPC		0.29
ClinPred		0.65	D
GERP RS		3.5
Varity_R		0.14
gMVP		0.88
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs80338853; hg19: chr11-71155082;