Submissions for variant NM_022436.3(ABCG5):c.1255C>T (p.Arg419Cys)

dbSNP: rs771475759

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000596623	SCV000705534	uncertain significance	not provided	2017-01-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002532484	SCV003252264	uncertain significance	Sitosterolemia	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 419 of the ABCG5 protein (p.Arg419Cys). This variant is present in population databases (rs771475759, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of sitosterolemia (PMID: 32041611, 32088153). ClinVar contains an entry for this variant (Variation ID: 499836). 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. This variant disrupts the p.Arg419 amino acid residue in ABCG5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11452359, 11855938, 21576934, 32862661). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701686	SCV005202282	uncertain significance	not specified	2024-07-29	criteria provided, single submitter	clinical testing	Variant summary: ABCG5 c.1255C>T (p.Arg419Cys) results in a non-conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251472 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCG5 causing Sitosterolemia (6.8e-05 vs 0.0032), allowing no conclusion about variant significance. c.1255C>T has been reported in the literature in individuals affected with Sitosterolemia (Okavor_2022, Desai_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33707850, 32942937, 32088153). ClinVar contains an entry for this variant (Variation ID: 499836). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.