rs104894090

Positions:

• chr8-38146051-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000349.3(STAR):​c.562C>T​(p.Arg188Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000471 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R188H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: STAR NM_000349.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 4.20

Genes affected

STAR (HGNC:11359): (steroidogenic acute regulatory protein) The protein encoded by this gene plays a key role in the acute regulation of steroid hormone synthesis by enhancing the conversion of cholesterol into pregnenolone. This protein permits the cleavage of cholesterol into pregnenolone by mediating the transport of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane. Mutations in this gene are a cause of congenital lipoid adrenal hyperplasia (CLAH), also called lipoid CAH. A pseudogene of this gene is located on chromosome 13. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000349.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 8-38146051-G-A is Pathogenic according to our data. Variant chr8-38146051-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-38146051-G-A is described in Lovd as [Likely_pathogenic]. Variant chr8-38146051-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAR	NM_000349.3	c.562C>T	p.Arg188Cys	missense_variant	5/7	ENST00000276449.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAR	ENST00000276449.9	c.562C>T	p.Arg188Cys	missense_variant	5/7	1	NM_000349.3	P1
STAR	ENST00000522050.1	c.499C>T	p.Arg167Cys	missense_variant	4/5	5
STAR	ENST00000520114.1	n.1049C>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251352 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135900

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000493 AC: 72 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.0000646 AC XY: 47 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74370

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000268 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital lipoid adrenal hyperplasia due to STAR deficency Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 26, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 16, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.98
MVP		0.96
MPC		0.97
ClinPred		0.89	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.4
Varity_R		0.86
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104894090; hg19: chr8-38003569;