Submissions for variant NM_000349.3(STAR):c.544C>T (p.Arg182Cys)

dbSNP: rs369232492

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665326	SCV000789427	likely pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2017-01-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001211857	SCV001383419	pathogenic	not provided	2024-02-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 182 of the STAR protein (p.Arg182Cys). This variant is present in population databases (rs369232492, gnomAD 0.006%). This missense change has been observed in individual(s) with lipoid adrenal hyperplasia (PMID: 16118340, 24790358, 24904850). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550550). 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%. This variant disrupts the p.Arg182 amino acid residue in STAR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11509019, 15546900). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
3billion, Medical Genetics	RCV000665326	SCV002521179	pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000550550). A different missense change at the same codon (p.Arg182His) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008995). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV000665326	SCV002802670	pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2024-01-29	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000665326	SCV004809922	pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2024-04-04	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000665326	SCV005329465	pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2023-06-02	criteria provided, single submitter	clinical testing	The observed missense c.544C>T(p.Arg182Cys) variant in STAR gene has been reported previously in homoygous and compound heterozygous state in multiple individuals affected with lipoid adrenal hyperplasia (Park HW, et al., 2013; Ishizu K, et al., 2008; Joshi R, et al., 2014). The p.Arg182Cys variant has been reported with allele frequency of 0.001% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Arg182Cys in STAR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 182 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. Another missense variant c.545G>A (p.Arg182His) on the same residue has been reported previously to be Pathogenic (Chen X, et al., 2005), suggesting that this residue might be of clinical significance. For these reasons, this variant has been classified as Pathogenic. In absence of another reportable variant in STAR gene, the molecular diagnosis is not confirmed. The same variant in STAR gene was previously detected in heterozygous state in mother [Mrs. SALLA LAKSHANA, id: 30406300477].
Natera, Inc.	RCV000665326	SCV002083262	pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2020-02-03	no assertion criteria provided	clinical testing