ClinVar Miner

Submissions for variant NM_000349.3(STAR):c.125dup (p.Thr44fs) (rs750549499)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000779556 SCV000916229 pathogenic Cholesterol monooxygenase (side-chain cleaving) deficiency 2017-05-10 criteria provided, single submitter clinical testing The STAR c.125dupG (p.Thr44HisfsTer3) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Thr44HisfsTer3 variant has been reported in three studies and is found in a total of seven patients with congenital adrenal hyperplasia (CAH), including in one in a homozygous state, in five (including one sibling pair) in a compound heterozygous state and in one in a heterozygous state in whom a second allele was not detected (Nakae et al. 1997; Shima et al. 2000; Flück et al. 2011). All seven patients were diagnosed with lipoid CAH. The p.Thr44HisfsTer3 variant was also found in the unaffected father of the sibling pair in a heterozygous state (Flück et al. 2011). Control data are unavailable for the p.Thr44HisfsTer3 variant, which is reported at a frequency of 0.000058 in the East Asian population of the Genome Aggregation Database but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Expression analysis in COS-1 cells demonstrated that the p.Thr44HisfsTer3 variant protein had a pregnenolone production rate comparable to the vector control and is therefore described as completely inactive (Flück et al. 2011). Based on the evidence from the literature and the potential impact of frameshift variants, the p.Thr44HisfsTer3 variant is classified as pathogenic for congenital adrenal hyperplasia, and has most often been reported in patients with the lipoid subtype. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000792850 SCV000932174 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr44Hisfs*3) in the STAR gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed to segregate with lipoid adrenal hyperplasia in a family (PMID: 21647419) and has been observed in individuals with lipoid adrenal hyperplasia (PMID: 9097960, 10700722). Loss-of-function variants in STAR are known to be pathogenic (PMID: 8948562). For these reasons, this variant has been classified as Pathogenic.

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