NM_001360.3(DHCR7):c.521T>C (p.Phe174Ser) AND Smith-Lemli-Opitz syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Sep 15, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000670698.11

Allele description [Variation Report for NM_001360.3(DHCR7):c.521T>C (p.Phe174Ser)]

NM_001360.3(DHCR7):c.521T>C (p.Phe174Ser)

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.521T>C (p.Phe174Ser)

HGVS:

NC_000011.10:g.71441332A>G
NG_012655.2:g.12100T>C
NM_001163817.2:c.521T>C
NM_001360.3:c.521T>CMANE SELECT
NP_001157289.1:p.Phe174Ser
NP_001351.2:p.Phe174Ser
NP_001351.2:p.Phe174Ser
LRG_340t1:c.521T>C
LRG_340:g.12100T>C
LRG_340p1:p.Phe174Ser
NC_000011.9:g.71152378A>G
NM_001360.2:c.521T>C

Protein change:

F174S

Links:

dbSNP: rs769218623

NCBI 1000 Genomes Browser:

rs769218623

Molecular consequence:

NM_001163817.2:c.521T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001360.3:c.521T>C - 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
SCV000795588	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Nov 9, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26969503, 15979035 Citation Link,
SCV001994827	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 18, 2021)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002231188	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 15, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15979035, 26969503, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000795588

Counsyl

criteria provided, single submitter

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

Uncertain significance
(Nov 9, 2017)

unknown

clinical testing

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

Citation Link,

SCV001994827

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 18, 2021)

paternal

clinical testing

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

SCV002231188

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 15, 2023)

germline

clinical testing

PubMed (3)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	paternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	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

Molecular studies in Portuguese patients with Smith-Lemli-Opitz syndrome and report of three new mutations in DHCR7.

Cardoso ML, Balreira A, Martins E, Nunes L, Cabral A, Marques M, Lima MR, Marques JS, Medeira A, Cordeiro I, Pedro S, Mota MC, Dionisi-Vici C, Santorelli FM, Jakobs C, Clayton PT, Vilarinho L.

Mol Genet Metab. 2005 Jul;85(3):228-35. Epub 2005 Apr 14.

PubMed [citation]

PMID:: 15979035

See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000795588.1

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

#	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 Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV001994827.1

#	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	paternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002231188.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 174 of the DHCR7 protein (p.Phe174Ser). This variant is present in population databases (rs769218623, gnomAD 0.01%). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 554967). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 15979035, 26969503). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant.

#	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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