rs1223603615

Positions:

• chr11-71441321-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_001360.3(DHCR7):​c.532A>T​(p.Ile178Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I178N) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.30

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity DHCR7_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_001360.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-71441320-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.532A>T	p.Ile178Phe	missense_variant	6/9	ENST00000355527.8	NP_001351.2
DHCR7	NM_001163817.2	c.532A>T	p.Ile178Phe	missense_variant	6/9		NP_001157289.1
DHCR7	XM_011544777.3	c.532A>T	p.Ile178Phe	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.532A>T	p.Ile178Phe	missense_variant	6/9	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.-54A>T		5_prime_UTR_variant	5/8			ENSP00000509319.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250988 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135724

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 20, 2024

Variant summary: DHCR7 c.532A>T (p.Ile178Phe) results in a non-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 4e-06 in 250988 control chromosomes (gnomAD). c.532A>T has been reported in the literature in the compound heterozygous state in individuals affected with Smith-Lemli-Opitz Syndrome (e.g. Haas_2005, Witsch-Baumgartner_2005). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15776424, 16435228). ClinVar contains an entry for this variant (Variation ID: 558484). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Smith-Lemli-Opitz syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

May 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	22
DANN	Benign	0.80
DEOGEN2	Uncertain	0.69	D;D;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.6	M;M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.31	N;N;N
REVEL	Pathogenic	0.70
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.36	T;T;.
Polyphen		0.95	P;P;.
Vest4		0.96
MutPred		0.62		Loss of stability (P = 0.2672);Loss of stability (P = 0.2672);.;
MVP		0.96
MPC		0.66
ClinPred		0.53	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.96

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: rs1223603615; hg19: chr11-71152367;