NM_001360.3(DHCR7):c.433A>C (p.Ile145Leu) AND Smith-Lemli-Opitz syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 29, 2023
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:: RCV000674923.12

Allele description [Variation Report for NM_001360.3(DHCR7):c.433A>C (p.Ile145Leu)]

NM_001360.3(DHCR7):c.433A>C (p.Ile145Leu)

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.433A>C (p.Ile145Leu)

HGVS:

NC_000011.10:g.71441420T>G
NG_012655.2:g.12012A>C
NM_001163817.2:c.433A>C
NM_001360.3:c.433A>CMANE SELECT
NP_001157289.1:p.Ile145Leu
NP_001351.2:p.Ile145Leu
NP_001351.2:p.Ile145Leu
LRG_340t1:c.433A>C
LRG_340:g.12012A>C
LRG_340p1:p.Ile145Leu
NC_000011.9:g.71152466T>G
NM_001360.2:c.433A>C

Protein change:

I145L

Links:

dbSNP: rs1555146475

NCBI 1000 Genomes Browser:

rs1555146475

Molecular consequence:

NM_001163817.2:c.433A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001360.3:c.433A>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
SCV001382270	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 29, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15954111, 20556518, 28492532
SCV002526395	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 10, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20556518, 15954111, 30925529, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001382270

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 29, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002526395

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 10, 2022)

germline

clinical testing

PubMed (4)
[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	germline	yes	1	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

Brain magnetic resonance imaging findings in Smith-Lemli-Opitz syndrome.

Lee RW, Conley SK, Gropman A, Porter FD, Baker EH.

Am J Med Genet A. 2013 Oct;161A(10):2407-19. doi: 10.1002/ajmg.a.36096. Epub 2013 Aug 5.

PubMed [citation]

PMID:: 23918729
PMCID:: PMC3787998

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000800339.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001382270.4

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

Description

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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DHCR7 protein function. ClinVar contains an entry for this variant (Variation ID: 558625). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 15954111, 20556518). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 145 of the DHCR7 protein (p.Ile145Leu).

#	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 DASA, SCV002526395.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

The c.433A>C;p.(Ile145Leu) missense change has been observed in affected individual(s) (PMID: 20556518; 15954111; 30925529) - PS4. This variant is not present in population databases:rs1555146475, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Ile145Leu) was detected in trans with a Pathogenic variant (PMID: 20556518; 15954111; 30925529) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 30925529) - PP1. In summary, the currently available evidence indicates that the variant is Pathogenic

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000800339	Counsyl	flagged submission Reason: Claim with insufficient supporting evidence Notes: None (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Jun 4, 2018)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23918729, 20556518 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000800339

Counsyl

flagged submission

Reason: Claim with insufficient supporting evidence

Notes: None

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

Uncertain significance
(Jun 4, 2018)

unknown

clinical testing

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

Citation Link

Last Updated: Oct 8, 2024

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