ClinVar Miner

Submissions for variant NM_000349.3(STAR):c.653C>T (p.Ala218Val)

gnomAD frequency: 0.00003  dbSNP: rs137852690
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001388088 SCV001588935 pathogenic not provided 2023-11-10 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 218 of the STAR protein (p.Ala218Val). This variant is present in population databases (rs137852690, gnomAD 0.008%). This missense change has been observed in individuals with congenital lipoid adrenal hyperplasia (PMID: 9097960, 10566637, 23748066). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8993). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change 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 RCV000009556 SCV002511480 pathogenic Congenital lipoid adrenal hyperplasia due to STAR deficency 2022-04-14 criteria provided, single submitter clinical testing Variant summary: STAR c.653C>T (p.Ala218Val) results in a non-conservative amino acid change located in the START domain (IPR002913) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 251340 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in STAR causing Congenital Lipoid Adrenal Hyperplasia (4e-05 vs 0.0035), allowing no conclusion about variant significance. c.653C>T has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Congenital Lipoid Adrenal Hyperplasia (example, Kang_2017, Wijaya_2021, Nakae_1997). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Nakae_1997). The most pronounced variant effect results in <10% of normal activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
3billion RCV000009556 SCV002572582 pathogenic Congenital lipoid adrenal hyperplasia due to STAR deficency 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 9097960). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.68). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: VCV000008993). A different missense change at the same codon (p.Ala218Thr) has been reported to be associated with STAR-related disorder (PMID: 31666050). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics RCV000009556 SCV005679049 pathogenic Congenital lipoid adrenal hyperplasia due to STAR deficency 2024-04-24 criteria provided, single submitter clinical testing
OMIM RCV000009556 SCV000029774 pathogenic Congenital lipoid adrenal hyperplasia due to STAR deficency 1999-11-01 no assertion criteria provided literature only
Natera, Inc. RCV000009556 SCV002083261 pathogenic Congenital lipoid adrenal hyperplasia due to STAR deficency 2020-10-16 no assertion criteria provided clinical testing

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