rs104894085

Positions:

• chr8-38144359-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000349.3(STAR):​c.772C>T​(p.Gln258Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000262 in 1,453,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: STAR NM_000349.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.71

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.1 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-38144359-G-A is Pathogenic according to our data. Variant chr8-38144359-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAR	NM_000349.3	c.772C>T	p.Gln258Ter	stop_gained	7/7	ENST00000276449.9	NP_000340.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAR	ENST00000276449.9	c.772C>T	p.Gln258Ter	stop_gained	7/7	1	NM_000349.3	ENSP00000276449	P1
STAR	ENST00000522050.1	c.615C>T	p.Thr205=	synonymous_variant	5/5	5		ENSP00000429009
STAR	ENST00000520114.1	n.2741C>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000471 AC: 11 AN: 233372 Hom.: 0 AF XY: 0.0000397 AC XY: 5 AN XY: 125954

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000632

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000262 AC: 38 AN: 1453146 Hom.: 0 Cov.: 30 AF XY: 0.0000305 AC XY: 22 AN XY: 722016

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000940

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital lipoid adrenal hyperplasia due to STAR deficency Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 15, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2000	- -
Pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2022	Variant summary: STAR c.772C>T (p.Gln258X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.7e-05 in 233372 control chromosomes (gnomAD), predominantly at a frequency of 0.00063 within the East Asian subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in STAR causing Congenital Lipoid Adrenal Hyperplasia (4.7e-05 vs 0.0035), allowing no conclusion about variant significance. c.772C>T has been reported in the literature in several homozygous and compound heterozygous individuals affected with Congenital Lipoid Adrenal Hyperplasia (e.g.Katsumata_1997, Nakae_1997, Amano_2017, Kang_2017), predominantly in those of East Asian ancestry, with evidence of a founder effect especially in Korean and Japanese populations (Amano_2017, Kang_2017). These data indicate that the variant is very likely to be associated with disease. When the variant was transfected into COS-1 cells, it did not magnify pregnenolone production like wildtype STAR protein; instead, the variant had the same activity as empty vector (Nakae_1997). Seperately, the variant was found incapable of interacting with binding partner SBP (StAR binding protein, Sugawara_2003). Five ClinVar submitters have assessed the variant since 2014: all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 19, 2017	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

This sequence change creates a premature translational stop signal (p.Gln258*) in the STAR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 28 amino acid(s) of the STAR protein. This variant is present in population databases (rs104894085, gnomAD 0.07%). This premature translational stop signal has been observed in individuals with lipoid adrenal hyperplasia (PMID: 8948562, 9097960, 22028173, 28467518). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8987). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A
Vest4		0.88
ClinPred		0.85	D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs104894085; hg19: chr8-38001877;