rs104894090
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_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
Consequence
NM_000349.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
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: 4AN: 152216Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251352Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135900
GnomAD4 exome AF: 0.0000493 AC: 72AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.0000646 AC XY: 47AN XY: 727246
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74370
ClinVar
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at