Submissions for variant NM_022437.3(ABCG8):c.1974C>G (p.Tyr658Ter)

gnomAD frequency: 0.00008  dbSNP: rs137852989

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000593346	SCV000708654	likely pathogenic	not provided	2017-05-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000593346	SCV002174440	uncertain significance	not provided	2024-12-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr658*) in the ABCG8 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the ABCG8 protein. This variant is present in population databases (rs137852989, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with sitosterolemia (PMID: 11099417). ClinVar contains an entry for this variant (Variation ID: 4969). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000005257	SCV003822409	uncertain significance	Sitosterolemia 1	2022-01-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004766981	SCV005381416	pathogenic	Sitosterolemia	2024-08-05	criteria provided, single submitter	clinical testing	Variant summary: ABCG8 c.1974C>G (p.Tyr658X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. The variant allele was found at a frequency of 2.4e-05 in 251406 control chromosomes. c.1974C>G has been reported in the literature in individuals affected with Sitosterolemia (example: Mariano_2019 and Lu_2001). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11452359, 31893465, 35549507). ClinVar contains an entry for this variant (Variation ID: 4969). Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000593346	SCV005413315	likely pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PM2, PM3, PVS1_strong
OMIM	RCV000005257	SCV000025435	pathogenic	Sitosterolemia 1	2000-12-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004742213	SCV005347347	likely pathogenic	ABCG8-related disorder	2024-05-01	no assertion criteria provided	clinical testing	The ABCG8 c.1974C>G variant is predicted to result in premature protein termination (p.Tyr658*). This variant has been reported in an individual with sitosterolemia, who also had a second ABCG8 premature termination variant (Berge et al. 2000. PubMed ID: 11099417). At PreventionGenetics, we have also observed the p.Tyr658* variant in the homozygous state in an individual with sitosterolemia. However, this variant is located just 15 amino acids upstream of the native termination codon, and no other premature termination variants have been reported downstream of this variant. This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in ABCG8 are expected to be pathogenic. This variant is interpreted as likely pathogenic.