VCV000430220.14 - ClinVar

NM_001360.3(DHCR7):c.655T>G (p.Tyr219Asp)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(3); Uncertain significance(2)

6 out of 7 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001360.3(DHCR7):c.655T>G (p.Tyr219Asp)

Variation ID: 430220 Accession: VCV000430220.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q13.4 11: 71439055 (GRCh38) [ NCBI UCSC ] 11: 71150101 (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	Jul 2, 2017	Feb 25, 2025	Jun 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001360.3:c.655T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001351.2:p.Tyr219Asp	missense
NM_001163817.2:c.655T>G	NP_001157289.1:p.Tyr219Asp	missense
NC_000011.10:g.71439055A>C
NC_000011.9:g.71150101A>C
NG_012655.2:g.14377T>G
LRG_340:g.14377T>G
LRG_340t1:c.655T>G	LRG_340p1:p.Tyr219Asp

... more HGVS ... less HGVS

Protein change

Y219D

Other names

Canonical SPDI

NC_000011.10:71439054:A: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.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA6162499 dbSNP: rs779896782 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		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	998	1013

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	Likely pathogenic (1)	criteria provided, single submitter	Apr 9, 2021	RCV000493359.3
Smith-Lemli-Opitz syndrome	Conflicting classifications of pathogenicity (5)	criteria provided, conflicting classifications	Jun 10, 2024	RCV000668765.14
not specified	Uncertain significance (1)	criteria provided, single submitter	Jun 7, 2022	RCV002271516.1

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 (Aug 16, 2017) C Contributing to aggregate classification	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Smith-Lemli-Opitz syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000793417.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (1) PubMed: 18249054
Likely pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Smith-Lemli-Opitz syndrome Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001163330.1 First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020
Uncertain significance (Jun 07, 2022) C Contributing to aggregate classification	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: SCV002555718.1 First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022	Publications: PubMed (1) PubMed: 18249054 Comment: Variant summary: DHCR7 c.655T>G (p.Tyr219Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more) Variant summary: DHCR7 c.655T>G (p.Tyr219Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251320 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.655T>G has been reported in the literature in an individual affected with Smith-Lemli-Opitz Syndrome in the compound heterozygous state (Jezela-Stanek_2008). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three submitters classified the variant as likely pathogenic/pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Likely pathogenic (Apr 09, 2021) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000582971.6 First in ClinVar: Jul 02, 2017 Last updated: Mar 04, 2023	Comment: Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico … (more) Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18249054, 23042628, 20556518) (less)
Pathogenic (Jun 15, 2023) C Contributing to aggregate classification	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: SCV002238197.4 First in ClinVar: Mar 28, 2022 Last updated: Feb 25, 2025	Publications: PubMed (1) PubMed: 18249054 Comment: 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, … (more) 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: 430220). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 18249054). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs779896782, gnomAD 0.002%). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 219 of the DHCR7 protein (p.Tyr219Asp). (less)
Likely pathogenic (Jun 10, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Smith-Lemli-Opitz syndrome Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV005629870.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025
Likely pathogenic (Sep 16, 2020) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Smith-Lemli-Opitz syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001460491.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Comment:

Variant summary: DHCR7 c.655T>G (p.Tyr219Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251320 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.655T>G has been reported in the literature in an individual affected with Smith-Lemli-Opitz Syndrome in the compound heterozygous state (Jezela-Stanek_2008). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three submitters classified the variant as likely pathogenic/pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18249054, 23042628, 20556518)

Comment:

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: 430220). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 18249054). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs779896782, gnomAD 0.002%). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 219 of the DHCR7 protein (p.Tyr219Asp).

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
Mild Smith-Lemli-Opitz syndrome: further delineation of 5 Polish cases and review of the literature.	Jezela-Stanek A	European journal of medical genetics	2008	PMID: 18249054

Text-mined citations for rs779896782 ...

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 Apr 08, 2025

ClinVar Genomic variation as it relates to human health

NM_001360.3(DHCR7):c.655T>G (p.Tyr219Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs779896782 ...