NM_001360.3(DHCR7):c.1351T>C (p.Cys451Arg) AND Smith-Lemli-Opitz syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002289056.5

Allele description [Variation Report for NM_001360.3(DHCR7):c.1351T>C (p.Cys451Arg)]

NM_001360.3(DHCR7):c.1351T>C (p.Cys451Arg)

Gene:

DHCR7:7-dehydrocholesterol reductase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q13.4

Genomic location:

Preferred name:

NM_001360.3(DHCR7):c.1351T>C (p.Cys451Arg)

HGVS:

NC_000011.10:g.71435452A>G
NG_012655.2:g.17980T>C
NM_001163817.2:c.1351T>C
NM_001360.3:c.1351T>CMANE SELECT
NP_001157289.1:p.Cys451Arg
NP_001351.2:p.Cys451Arg
NP_001351.2:p.Cys451Arg
LRG_340t1:c.1351T>C
LRG_340:g.17980T>C
LRG_340p1:p.Cys451Arg
NC_000011.9:g.71146498A>G
NM_001360.2:c.1351T>C
NM_001360.2:c.1351T>C

Protein change:

C451R

Molecular consequence:

NM_001163817.2:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001360.3:c.1351T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Smith-Lemli-Opitz syndrome (SLOS)
Synonyms:: LETHAL ACRODYSGENITAL SYNDROME; POLYDACTYLY, SEX REVERSAL, RENAL HYPOPLASIA, AND UNILOBAR LUNG; RUTLEDGE LETHAL MULTIPLE CONGENITAL ANOMALY SYNDROME; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010035; MedGen: C0175694; Orphanet: 818; OMIM: 270400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002581451	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 10, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003440565	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31840946, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002581451

MGZ Medical Genetics Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 10, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003440565

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 31, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Smith-Lemli-Opitz syndrome - Fetal phenotypes with special reference to the syndrome-specific internal malformation pattern.

Schoner K, Witsch-Baumgartner M, Behunova J, Petrovic R, Bald R, Kircher SG, Ramaswamy A, Kluge B, Meyer-Wittkopf M, Schmitz R, Fritz B, Zschocke J, Laccone F, Rehder H.

Birth Defects Res. 2020 Jan 15;112(2):175-185. doi: 10.1002/bdr2.1620. Epub 2019 Dec 16.

PubMed [citation]

PMID:: 31840946
PMCID:: PMC7432161

See all PubMed Citations (3)

Details of each submission

From MGZ Medical Genetics Center, SCV002581451.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003440565.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 451 of the DHCR7 protein (p.Cys451Arg). This variant is present in population databases (rs761458977, gnomAD 0.0009%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 31840946). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1709241). 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 with a positive predictive value of 95%. This variant disrupts the p.Cys451 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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