Submissions for variant NM_000349.3(STAR):c.661G>A (p.Gly221Ser)

gnomAD frequency: 0.00004  dbSNP: rs139081695

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000819131	SCV000959774	pathogenic	not provided	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 221 of the STAR protein (p.Gly221Ser). This variant is present in population databases (rs139081695, gnomAD 0.009%). This missense change has been observed in individual(s) with STAR-related conditions (PMID: 21647419, 32252217). 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. ClinVar contains an entry for this variant (Variation ID: 661662). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STAR protein function. Experimental studies have shown that this missense change affects STAR function (PMID: 21647419). This variant disrupts the p.Gly221 amino acid residue in STAR. Other variant(s) that disrupt this residue have been observed in individuals with STAR-related conditions (PMID: 20444910), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001275354	SCV002023679	likely pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2023-08-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001275354	SCV002775410	likely pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2021-11-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001275354	SCV003844303	likely pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2023-02-28	criteria provided, single submitter	clinical testing	Variant summary: STAR c.661G>A (p.Gly221Ser) 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. The variant allele was found at a frequency of 4e-05 in 251406 control chromosomes (gnomAD). 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.661G>A has been reported in the literature in compound heterozygous individuals affected with Congenital Lipoid Adrenal Hyperplasia (Fluck_2011, Bae_2020, Zhang_2020, Buonocore_2021). In addition, this variant co-segregated with Congenital Lipoid Adrenal Hyperplasia in one family (Fluck_2011). These data indicate that the variant is likely to be associated with disease. At least two functional studies report this variant results in reducing enzyme activity compared to wild-type in vitro (Fluck_2011, Zhang_2020). Four ClinVar submitters (evaluation after 2014) cite this variant as pathogenic (n=1) and likely pathogenic (n=3). Additionally, another variant (p.G221D) in the same residual was reported in patients and showed reactivity 6% of WT (Bae_2020, HGMD database), suggesting this residue is functional important Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc.	RCV001275354	SCV001460461	likely pathogenic	Congenital lipoid adrenal hyperplasia due to STAR deficency	2020-09-16	no assertion criteria provided	clinical testing