Submissions for variant NM_000443.4(ABCB4):c.3764C>T (p.Thr1255Met)

gnomAD frequency: 0.00016  dbSNP: rs147577035

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV004531153	SCV004120745	uncertain significance	ABCB4-related disorder	2023-07-31	criteria provided, single submitter	clinical testing	The ABCB4 c.3764C>T variant is predicted to result in the amino acid substitution p.Thr1255Met. This variant, also known as c.3785C>T (p.Thr1262Met), was reported in the compound heterozygous state in an individual with adult-onset liver disease (Nayagam et al 2022. PubMed ID: 35894240 Table S1). This variant is reported in 0.048% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-87031488-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Mayo Clinic Laboratories, Mayo Clinic	RCV001355572	SCV004224021	uncertain significance	not provided	2023-05-09	criteria provided, single submitter	clinical testing	PM2
Invitae	RCV001355572	SCV004281880	uncertain significance	not provided	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1255 of the ABCB4 protein (p.Thr1255Met). This variant is present in population databases (rs147577035, gnomAD 0.05%). This missense change has been observed in individual(s) with ABCB4-related conditions (PMID: 35894240). This variant is also known as c.3785C>T (p.Thr1262Met). ClinVar contains an entry for this variant (Variation ID: 1049446). 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 ABCB4 protein function. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355572	SCV001550496	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ABCB4 p.Thr1255Met variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs147577035) and was also found in control databases in 16 of 282790 chromosomes at a frequency of 0.000057 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 12 of 24968 chromosomes (freq: 0.000481), Latino in 2 of 35440 chromosomes (freq: 0.000056), South Asian in 1 of 30616 chromosomes (freq: 0.000033) and European (non-Finnish) in 1 of 129108 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) and Other populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Thr1255 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.