Submissions for variant NM_000349.3(STAR):c.714del (p.Lys238fs)

dbSNP: rs1417088430

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000674399	SCV000799726	likely pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2018-05-03	criteria provided, single submitter	clinical testing
Invitae	RCV001039943	SCV001203494	pathogenic	not provided	2023-08-22	criteria provided, single submitter	clinical testing	This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change results in a frameshift in the STAR gene (p.Lys238Asnfs*83). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the STAR protein and extend the protein by 34 additional amino acid residues. This frameshift has been observed in individual(s) with congenital lipoid adrenal hyperplasia (PMID: 9077535, 9097960, 10215405, 26827627). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as 838del. ClinVar contains an entry for this variant (Variation ID: 558171). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects STAR function (PMID: 9097960). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000674399	SCV004028620	pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: STAR c.714delA (p.Lys238AsnfsX83) causes a frameshift which alters the last 48 amino acids of the protein in the START domain (IPR002913) and results in an extension of the protein. The variant allele was found at a frequency of 4e-06 in 251482 control chromosomes (gnomAD). c.714delA has been reported in the literature in individuals affected with Congenital Lipoid Adrenal Hyperplasia who were compound heterozygous with another pathogenic variant (Nakae_1997, Qiu_2005, Amano_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that cells transfected with the variant protein had no steroidogenesis enhancing activity (Nakae_2017). The following publications have been ascertained in the context of this evaluation (PMID: 9097960, 15347444, 28546232). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.