Submissions for variant NM_000349.3(STAR):c.562C>T (p.Arg188Cys)

gnomAD frequency: 0.00003  dbSNP: rs104894090

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000009560	SCV000794460	pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2017-09-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812202	SCV000952507	pathogenic	not provided	2024-07-10	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 188 of the STAR protein (p.Arg188Cys). This variant is present in population databases (rs104894090, gnomAD 0.03%). This missense change has been observed in individuals with nonclassic lipoid congenital adrenal hyperplasia or primary adrenal insufficiency (PMID: 16968793, 19773404, 20444910, 26650942, 28637490, 29576868). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8997). 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 not expected to disrupt STAR protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects STAR function (PMID: 16968793, 20444910). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000812202	SCV001819354	pathogenic	not provided	2023-02-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate decreased binding to cholesterol and reduced enzymatic activity (Baker et al., 2006); 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: 34758253, 20444910, 26650942, 28637490, 17301050, 29576868, 34426522, 32841165, 33227378, 16968793, 19773404)
Revvity Omics, Revvity	RCV000009560	SCV002021968	pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2022-11-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000009560	SCV002803333	pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2024-04-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000009560	SCV004803354	pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2024-01-15	criteria provided, single submitter	clinical testing	Variant summary: STAR c.562C>T (p.Arg188Cys) results in a non-conservative amino acid change located in the START domain (IPR002913) of 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 4.4e-05 in 251552 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in STAR causing Congenital Lipoid Adrenal Hyperplasia (4.4e-05 vs 0.0035), allowing no conclusion about variant significance. c.562C>T has been reported in the literature in multiple bi-allelic individuals affected with Congenital Lipoid Adrenal Hyperplasia (examples: Baker_2006, Sahakitrungruang_2010, Fluck_2011, Zhang_2021). These data indicate that the variant is very likely to be associated with disease. Multiple publications have reported experimental evidence that this variant disrupts normal protein activity (Baker_2006 and Sahakitrungruang_2010). The following publications have been ascertained in the context of this evaluation (PMID: 16968793, 20444910, 33227378, 21691943, 21951701). ClinVar contains an entry for this variant (Variation ID: 8997). Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000009560	SCV005073905	pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency		criteria provided, single submitter	clinical testing	The observed missense c.562C>T(p.Arg188Cys) variant in STAR gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with Lipoid adrenal hyperplasia (Lu et al., 2022). Experimental studies have shown that this missense change affects STAR function (Sahakitrungruang et al., 2010). This variant is reported with the allele frequency of 0.004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). The amino acid Arg at position 188 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg188Cys in STAR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000009560	SCV000029778	pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2006-12-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000009560	SCV001460462	pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000812202	SCV001552195	pathogenic	not provided		no assertion criteria provided	clinical testing	The STAR p.R188C variant was identified in the literature in individuals and families with nonclassic lipoid congenital adrenal hyperplasia, chronic adrenal insufficiency, and primary/acute adrenal insufficiency in the homozygous or compound heterozygous state (Baker_2006_PMID:16968793; Metherell_2009_PMID:19773404; Sahakitrungruang_2011_PMID: 20444910; Tsai_2015_PMID:26650942; Bizzarri_2017_PMID:28637490; Burget_2018_PMID:29576868). The variant was identified in dbSNP (ID: rs104894090), LOVD 3.0 (classified as likely pathogenic) and ClinVar (classified as pathogenic by Counsyl, Invitae, and OMIM, and associated with cholesterol monooxygenase (side-chain cleaving) deficiency and lipoid congenital adrenal hyperplasia). The variant was identified in control databases in 11 of 251352 chromosomes at a frequency of 0.00004376 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 8 of 30616 chromosomes (freq: 0.000261), African in 1 of 16244 chromosomes (freq: 0.000062) and European (non-Finnish) in 2 of 113662 chromosomes (freq: 0.000018), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. However, the p.Arg188 residue is conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. Further, functional studies of the STAR p.R188C mutant protein have demonstrated reduced protein activity and cholesterol-binding capacity (Baker_2006_PMID:16968793; Sahakitrungruang_2011_PMID: 20444910). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Genomics England Pilot Project, Genomics England	RCV000009560	SCV001760208	pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency		no assertion criteria provided	clinical testing