NM_001360.3(DHCR7):c.1405C>T (p.Arg469Cys) AND Smith-Lemli-Opitz syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 11, 2022
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:: RCV000665167.5

Allele description [Variation Report for NM_001360.3(DHCR7):c.1405C>T (p.Arg469Cys)]

NM_001360.3(DHCR7):c.1405C>T (p.Arg469Cys)

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.1405C>T (p.Arg469Cys)

HGVS:

NC_000011.10:g.71435398G>A
NG_012655.2:g.18034C>T
NM_001163817.2:c.1405C>T
NM_001360.3:c.1405C>TMANE SELECT
NP_001157289.1:p.Arg469Cys
NP_001351.2:p.Arg469Cys
NP_001351.2:p.Arg469Cys
LRG_340t1:c.1405C>T
LRG_340:g.18034C>T
LRG_340p1:p.Arg469Cys
NC_000011.9:g.71146444G>A
NM_001360.2:c.1405C>T

Protein change:

R469C

Links:

dbSNP: rs148660993

NCBI 1000 Genomes Browser:

rs148660993

Molecular consequence:

NM_001163817.2:c.1405C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001360.3:c.1405C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000789237	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Jan 24, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001414729	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 11, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24813812, 28492532
SCV002092985	Natera, Inc.	no assertion criteria provided	Uncertain significance (May 24, 2018)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000789237

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(Jan 24, 2017)

unknown

clinical testing

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

Citation Link,

SCV001414729

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 11, 2022)

germline

clinical testing

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

SCV002092985

Natera, Inc.

no assertion criteria provided

Uncertain significance
(May 24, 2018)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	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

Determination of the allelic frequency in Smith-Lemli-Opitz syndrome by analysis of massively parallel sequencing data sets.

Cross JL, Iben J, Simpson CL, Thurm A, Swedo S, Tierney E, Bailey-Wilson JE, Biesecker LG, Porter FD, Wassif CA.

Clin Genet. 2015 Jun;87(6):570-5. doi: 10.1111/cge.12425. Epub 2014 Jun 6.

PubMed [citation]

PMID:: 24813812
PMCID:: PMC4225182

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Counsyl, SCV000789237.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001414729.2

#	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 arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 469 of the DHCR7 protein (p.Arg469Cys). This variant is present in population databases (rs148660993, gnomAD 0.02%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 24813812). ClinVar contains an entry for this variant (Variation ID: 550425). 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.

#	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

From Natera, Inc., SCV002092985.1

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

#	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: Mar 4, 2023

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