VCV000008995.11 - ClinVar

NM_000349.3(STAR):c.545G>A (p.Arg182His)

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.

(8)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000349.3(STAR):c.545G>A (p.Arg182His)

Variation ID: 8995 Accession: VCV000008995.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p11.23 8: 38146068 (GRCh38) [ NCBI UCSC ] 8: 38003586 (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	Apr 4, 2013	Sep 16, 2024	Jan 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000349.3:c.545G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000340.2:p.Arg182His	missense
NC_000008.11:g.38146068C>T
NC_000008.10:g.38003586C>T
NG_011827.1:g.10015G>A

Protein change

R182H

Other names

Canonical SPDI

NC_000008.11:38146067:C:T

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.

Links

ClinGen: CA120041 OMIM: 600617.0010 dbSNP: rs104894086 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.
STAR		-	-	GRCh38 GRCh37	366	448

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.
Congenital lipoid adrenal hyperplasia due to STAR deficency	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Feb 9, 2021	RCV000009558.8
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 4, 2024	RCV000518086.9

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.
Pathogenic (Aug 09, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000615515.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (16) PubMed: 26523528‚ 21846663‚ 26827627‚ 21164258‚ 22903695‚ 28637490‚ 22083155‚ 24904850‚ 12725533‚ 25883920‚ 16103714‚ 19245813‚ 15985476‚ 11509019‚ 15546900‚ 17301050
Pathogenic (Jan 19, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital Accession: SCV002525604.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022	Comment: This is a recurrent pathogenic variant that has previously been reported in the homozygous state in multiple unrelated individuals with STaR deficiency (PMID: 15546900, PMID: … (more) This is a recurrent pathogenic variant that has previously been reported in the homozygous state in multiple unrelated individuals with STaR deficiency (PMID: 15546900, PMID: 11509019, PMID: 26523528, PMID: 28870780). The c.545G>A variant is predicted to substitute the arginine at position 182 with histidine. The Arg182 is a highly conserved amino acid position within a critical functional domain (PMID: 11509019). Experimental studies have demonstrated that the p.Arg182His change impairs protein function (PMID: 15546900). (less) Clinical Features: Congenital adrenal hyperplasia (present)
Pathogenic (Feb 09, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital lipoid adrenal hyperplasia due to STAR deficency Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002021970.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Nov 10, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000950951.3 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 11509019‚ 15546900 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 182 of the STAR protein (p.Arg182His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 182 of the STAR protein (p.Arg182His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with congenital lipoid adrenal hyperplasia (PMID: 11509019, 15546900). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8995). 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 STAR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects STAR function (PMID: 15546900). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Jan 18, 2018)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Congenital lipoid adrenal hyperplasia due to STAR deficency Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000797248.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (3) PubMed: 17301050‚ 26523528‚ 15546900
Pathogenic (Jan 04, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005201955.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Comment: Published functional studies demonstrate a damaging effect on protein activity (PMID: 17301050, 15546900); In silico analysis supports that this missense variant has a deleterious effect … (more) Published functional studies demonstrate a damaging effect on protein activity (PMID: 17301050, 15546900); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28780348, 17301050, 15546900, 33227378, 32784047, 28870780, 26523528, 21846663, 25883920, 11509019, 24904850, 22083155, 28637490, 22903695, 19245813, 15985476, 26827627, 28467518) (less)
Pathogenic (Feb 01, 2005)	no assertion criteria provided Method: literature only	LIPOID CONGENITAL ADRENAL HYPERPLASIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029776.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 15546900‚ 11509019 Comment on evidence: Among 8 patients with congenital lipoid adrenal hyperplasia (201710) from 6 apparently unrelated Saudi Arabian families, Chen et al. (2005) reported that 7 were homozygous … (more) Among 8 patients with congenital lipoid adrenal hyperplasia (201710) from 6 apparently unrelated Saudi Arabian families, Chen et al. (2005) reported that 7 were homozygous for an arg182-to-his (R182H) mutation in the steroidogenic acute regulatory protein (STAR). Onset of symptoms ranged from 1 month to 14 months. The R182H mutation was recreated in a human STAR cDNA expression vector and found to be wholly inactive in a standard assay of COS-1 cells cotransfected with the cholesterol side-chain cleavage enzyme system. Thus, the loss of all assayable activity in vitro correlated poorly with the later onset of clinical symptoms in these patients. Chen et al. (2005) concluded that lipoid CAH may present much later in life than previously thought. Achermann et al. (2001) described this mutation in a patient from Qatar with onset of clinical symptoms and laboratory evidence of salt loss noted at 3 weeks of age. (less)
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Congenital lipoid adrenal hyperplasia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001460463.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Comment:

This is a recurrent pathogenic variant that has previously been reported in the homozygous state in multiple unrelated individuals with STaR deficiency (PMID: 15546900, PMID: 11509019, PMID: 26523528, PMID: 28870780). The c.545G>A variant is predicted to substitute the arginine at position 182 with histidine. The Arg182 is a highly conserved amino acid position within a critical functional domain (PMID: 11509019). Experimental studies have demonstrated that the p.Arg182His change impairs protein function (PMID: 15546900).

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 182 of the STAR protein (p.Arg182His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with congenital lipoid adrenal hyperplasia (PMID: 11509019, 15546900). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8995). 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 STAR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects STAR function (PMID: 15546900). For these reasons, this variant has been classified as Pathogenic.

Comment:

Published functional studies demonstrate a damaging effect on protein activity (PMID: 17301050, 15546900); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28780348, 17301050, 15546900, 33227378, 32784047, 28870780, 26523528, 21846663, 25883920, 11509019, 24904850, 22083155, 28637490, 22903695, 19245813, 15985476, 26827627, 28467518)

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
Lipoid congenital adrenal hyperplasia by steroidogenic acute regulatory protein (STAR) gene mutation in an Italian infant: an uncommon cause of adrenal insufficiency.	Bizzarri C	Italian journal of pediatrics	2017	PMID: 28637490
Identification of five novel STAR variants in ten Chinese patients with congenital lipoid adrenal hyperplasia.	Huang Z	Steroids	2016	PMID: 26827627
Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort.	Guran T	The Journal of clinical endocrinology and metabolism	2016	PMID: 26523528
Clinical and molecular review of atypical congenital adrenal hyperplasia.	Sahakitrungruang T	Annals of pediatric endocrinology & metabolism	2015	PMID: 25883920
p.R182C mutation in Korean twin with congenital lipoid adrenal hyperplasia.	Park HW	Annals of pediatric endocrinology & metabolism	2013	PMID: 24904850
Map of autosomal recessive genetic disorders in Saudi Arabia: concepts and future directions.	Al-Owain M	American journal of medical genetics. Part A	2012	PMID: 22903695
Congenital lipoid adrenal hyperplasia (a rare form of adrenal insufficiency and ambiguous genitalia) caused by a novel mutation of the steroidogenic acute regulatory protein gene.	Lekarev O	European journal of pediatrics	2012	PMID: 22083155
High allele frequency of the p.Q258X mutation and identification of a novel mis-splicing mutation in the STAR gene in Korean patients with congenital lipoid adrenal hyperplasia.	Kim JM	European journal of endocrinology	2011	PMID: 21846663
Functional and physiological consequences of StAR deficiency: role in lipoid congenital adrenal hyperplasia.	King SR	Endocrine development	2011	PMID: 21164258
Steroidogenic acute regulatory protein in white sturgeon (Acipenser transmontanus): cDNA cloning, sites of expression and transcript abundance in corticosteroidogenic tissue after an acute stressor.	Kusakabe M	General and comparative endocrinology	2009	PMID: 19245813
Cholesterol binding does not predict activity of the steroidogenic acute regulatory protein, StAR.	Baker BY	The Journal of biological chemistry	2007	PMID: 17301050
Disorders of androgen synthesis--from cholesterol to dehydroepiandrosterone.	Miller WL	Medical principles and practice : international journal of the Kuwait University, Health Science Centre	2005	PMID: 16103714
A novel mutation L260P of the steroidogenic acute regulatory protein gene in three unrelated patients of Swiss ancestry with congenital lipoid adrenal hyperplasia.	Flück CE	The Journal of clinical endocrinology and metabolism	2005	PMID: 15985476
A genetic isolate of congenital lipoid adrenal hyperplasia with atypical clinical findings.	Chen X	The Journal of clinical endocrinology and metabolism	2005	PMID: 15546900
Structural genomics of lipid signaling domains.	Tsujishita Y	Oncology research	2003	PMID: 12725533
Molecular and structural analysis of two novel StAR mutations in patients with lipoid congenital adrenal hyperplasia.	Achermann JC	Molecular genetics and metabolism	2001	PMID: 11509019
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Text-mined citations for rs104894086 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000349.3(STAR):c.545G>A (p.Arg182His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104894086 ...