11-71435815-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001360.3(DHCR7):c.988G>A(p.Val330Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,603,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V330V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12
• Conservation: PhyloP100: 3.28

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 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_001360.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39428446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHCR7	NM_001360.3	c.988G>A	p.Val330Met	missense_variant	9/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.988G>A	p.Val330Met	missense_variant	9/9
DHCR7	XM_011544777.3	c.1122G>A	p.Pro374=	synonymous_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.988G>A	p.Val330Met	missense_variant	9/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152204 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000364 AC: 87 AN: 239088 Hom.: 0 AF XY: 0.000367 AC XY: 48 AN XY: 130966

Gnomad AFR exome AF: 0.000268

Gnomad AMR exome AF: 0.000643

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.000103

Gnomad NFE exome AF: 0.000496

Gnomad OTH exome AF: 0.000679

GnomAD4 exome AF: 0.000409 AC: 594 AN: 1451442 Hom.: 0 Cov.: 37 AF XY: 0.000420 AC XY: 303 AN XY: 720604

Gnomad4 AFR exome AF: 0.0000900

Gnomad4 AMR exome AF: 0.000651

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.000455

Gnomad4 OTH exome AF: 0.000400

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152322 Hom.: 0 Cov.: 35 AF XY: 0.000457 AC XY: 34 AN XY: 74472

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000250 Hom.: 0

Bravo AF: 0.000370

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000467 AC: 4

ExAC AF: 0.000330 AC: 40

EpiCase AF: 0.000654

EpiControl AF: 0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Smith-Lemli-Opitz syndrome Uncertain:6

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2022	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 330 of the DHCR7 protein (p.Val330Met). This variant is present in population databases (rs139724817, gnomAD 0.06%). This missense change has been observed in individual(s) with Smith–Lemli–Opitz syndrome (PMID: 12270273). ClinVar contains an entry for this variant (Variation ID: 420113). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 23, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2022	Reported previously in an individual with psychomotor regression and multiple congenital abnormalities suggestive of Smith-Lemli-Opitz syndrome who had a second DHCR7 variant identified on the opposite allele; however, this patient's serum 7-DHC concentration was 100 fold lower than typical mean serum levels for affected individuals, and significantly lower than in the other patients reported in the study (Patrono et al., 2002); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23042628, 29300326, 24813812, 27401223, 15670717, 28250423, 12270273, 34426522) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 11, 2022

Variant summary: DHCR7 c.988G>A (p.Val330Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 239088 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (0.00036 vs 0.0043), allowing no conclusion about variant significance. c.988G>A has been reported in the literature in individuals affected with Smith-Lemli-Opitz Syndrome (example, Patrono_2002) and autism (example, Saskin_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hepatoblastoma Uncertain:1

Uncertain significance, no assertion criteria provided

research

Molecular Oncology - Human Genetics Lab, University of Sao Paulo

-

- -

DHCR7-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 14, 2023

The DHCR7 c.988G>A variant is predicted to result in the amino acid substitution p.Val330Met. This variant has been reported in a patient with suspected Smith-Lemli-Opitz syndrome (Patrono et al. 2002. PubMed ID: 12270273), in two patients in a large autism cohort (Table S2, Saskin et al. 2017. PubMed ID: 28250423), and in two patients with hepatoblastoma (Aguiar et al. 2022. PubMed ID: 35495172). In all cases pathogenicity was not clearly established. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.3	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.82
MVP		0.93
MPC		0.55
ClinPred		0.28	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.32
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs139724817; hg19: chr11-71146861; COSMIC: COSV62795117; COSMIC: COSV62795117;