rs137852690
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000349.3(STAR):c.653C>T(p.Ala218Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000349.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STAR | NM_000349.3 | c.653C>T | p.Ala218Val | missense_variant, splice_region_variant | 6/7 | ENST00000276449.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STAR | ENST00000276449.9 | c.653C>T | p.Ala218Val | missense_variant, splice_region_variant | 6/7 | 1 | NM_000349.3 | P1 | |
STAR | ENST00000522050.1 | c.586+650C>T | intron_variant | 5 | |||||
STAR | ENST00000520114.1 | n.1787C>T | non_coding_transcript_exon_variant | 4/4 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251340Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135852
GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461784Hom.: 0 Cov.: 36 AF XY: 0.0000509 AC XY: 37AN XY: 727198
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74334
ClinVar
Submissions by phenotype
Congenital lipoid adrenal hyperplasia due to STAR deficency Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1999 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 14, 2022 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at