VCV000445437.35 - ClinVar

NM_001360.3(DHCR7):c.719A>G (p.Asn240Ser)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(12)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001360.3(DHCR7):c.719A>G (p.Asn240Ser)

Variation ID: 445437 Accession: VCV000445437.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q13.4 11: 71438991 (GRCh38) [ NCBI UCSC ] 11: 71150037 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 5, 2017	Oct 20, 2024	Dec 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001360.3:c.719A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001351.2:p.Asn240Ser	missense
NM_001163817.2:c.719A>G	NP_001157289.1:p.Asn240Ser	missense
NC_000011.10:g.71438991T>C
NC_000011.9:g.71150037T>C
NG_012655.2:g.14441A>G
LRG_340:g.14441A>G
LRG_340t1:c.719A>G	LRG_340p1:p.Asn240Ser

... more HGVS ... less HGVS

Protein change

N240S

Other names

Canonical SPDI

NC_000011.10:71438990:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00016

The Genome Aggregation Database (gnomAD), exomes 0.00016

The Genome Aggregation Database (gnomAD) 0.00019

Trans-Omics for Precision Medicine (TOPMed) 0.00019

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038

Links

ClinGen: CA6162481 dbSNP: rs148609143 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
DHCR7		-	-	GRCh38 GRCh37	937	952

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Uncertain significance (5)	criteria provided, multiple submitters, no conflicts	Dec 30, 2023	RCV000513933.31
Smith-Lemli-Opitz syndrome	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Jun 20, 2022	RCV000763769.18
not specified	Uncertain significance (1)	criteria provided, single submitter	Jun 3, 2022	RCV002271517.8
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Jan 24, 2018	RCV002314895.9
DHCR7-related disorder	Uncertain significance (1)	no assertion criteria provided	May 9, 2024	RCV004748797.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (May 08, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000609803.1 First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017
Uncertain significance (Jun 14, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000861907.1 First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DHCR7 Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Smith-Lemli-Opitz syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894665.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Aug 09, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002061513.2 First in ClinVar: Jan 22, 2022 Last updated: Feb 11, 2022	Comment: PP3, PM2
Uncertain significance (Jun 03, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002555618.1 First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022	Publications: PubMed (2) PubMed: 29368431‚ 24813812 Comment: Variant summary: DHCR7 c.719A>G (p.Asn240Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more) Variant summary: DHCR7 c.719A>G (p.Asn240Ser) results in a 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 0.00016 in 251374 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (0.00016 vs 0.0043), allowing no conclusion about variant significance. c.719A>G has been reported in the literature in one individual affected with Cardiac defect (Hauser_2018). The report does not provide unequivocal conclusions about association of the variant with Smith-Lemli-Opitz Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Jun 20, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Smith-Lemli-Opitz syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000947860.3 First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023	Comment: This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 240 of the DHCR7 protein (p.Asn240Ser). … (more) This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 240 of the DHCR7 protein (p.Asn240Ser). This variant is present in population databases (rs148609143, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with DHCR7-related conditions. ClinVar contains an entry for this variant (Variation ID: 445437). 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. (less)
Uncertain significance (Jan 24, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000848322.5 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 24813812 Comment: The p.N240S variant (also known as c.719A>G), located in coding exon 5 of the DHCR7 gene, results from an A to G substitution at nucleotide … (more) The p.N240S variant (also known as c.719A>G), located in coding exon 5 of the DHCR7 gene, results from an A to G substitution at nucleotide position 719. The asparagine at codon 240 is replaced by serine, an amino acid with highly similar properties. In one study that aimed to determine the allele carrier frequency of Smith-Lemli-Opitz syndrome (SLOS), this variant was identified in the ESP population database cohort (Cross JL et al. Clin. Genet., 2015 Jun;87:570-5). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. (less)
Uncertain significance (Dec 30, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001765850.5 First in ClinVar: Aug 07, 2021 Last updated: Sep 29, 2024	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23603282, 24813812) (less)
Uncertain significance (Jun 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Smith-Lemli-Opitz syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003829078.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Jan 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004137202.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: DHCR7: PP3 Number of individuals with the variant: 1
Uncertain significance (May 11, 2018)	no assertion criteria provided Method: clinical testing	Smith-Lemli-Opitz syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001458014.1 First in ClinVar: Jan 01, 2021 Last updated: Jan 01, 2021
Uncertain significance (May 09, 2024)	no assertion criteria provided Method: clinical testing	DHCR7-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005364960.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The DHCR7 c.719A>G variant is predicted to result in the amino acid substitution p.Asn240Ser. This variant has been reported in a carrier study of the … (more) The DHCR7 c.719A>G variant is predicted to result in the amino acid substitution p.Asn240Ser. This variant has been reported in a carrier study of the DHCR7 gene (Cross et al. 2015. PubMed ID: 24813812); however, to our knowledge, this variant has not been reported in individuals with Smith-Lemli-Opitz syndrome. This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Comment:

Variant summary: DHCR7 c.719A>G (p.Asn240Ser) results in a 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 0.00016 in 251374 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (0.00016 vs 0.0043), allowing no conclusion about variant significance. c.719A>G has been reported in the literature in one individual affected with Cardiac defect (Hauser_2018). The report does not provide unequivocal conclusions about association of the variant with Smith-Lemli-Opitz Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 240 of the DHCR7 protein (p.Asn240Ser). This variant is present in population databases (rs148609143, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with DHCR7-related conditions. ClinVar contains an entry for this variant (Variation ID: 445437). 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.

Comment:

The p.N240S variant (also known as c.719A>G), located in coding exon 5 of the DHCR7 gene, results from an A to G substitution at nucleotide position 719. The asparagine at codon 240 is replaced by serine, an amino acid with highly similar properties. In one study that aimed to determine the allele carrier frequency of Smith-Lemli-Opitz syndrome (SLOS), this variant was identified in the ESP population database cohort (Cross JL et al. Clin. Genet., 2015 Jun;87:570-5). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23603282, 24813812)

Comment:

The DHCR7 c.719A>G variant is predicted to result in the amino acid substitution p.Asn240Ser. This variant has been reported in a carrier study of the DHCR7 gene (Cross et al. 2015. PubMed ID: 24813812); however, to our knowledge, this variant has not been reported in individuals with Smith-Lemli-Opitz syndrome. This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Experience with genomic sequencing in pediatric patients with congenital cardiac defects in a large community hospital.	Hauser NS	Molecular genetics & genomic medicine	2018	PMID: 29368431
Determination of the allelic frequency in Smith-Lemli-Opitz syndrome by analysis of massively parallel sequencing data sets.	Cross JL	Clinical genetics	2015	PMID: 24813812
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DHCR7	-	-	-	-

Text-mined citations for rs148609143 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_001360.3(DHCR7):c.719A>G (p.Asn240Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs148609143 ...