Submissions for variant NM_000477.7(ALB):c.725G>A (p.Arg242His)

gnomAD frequency: 0.00008  dbSNP: rs75002628

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000019886	SCV000267207	uncertain significance	Hyperthyroxinemia, familial dysalbuminemic	2016-03-18	criteria provided, single submitter	reference population
GeneDx	RCV001753423	SCV001986354	uncertain significance	not provided	2021-04-08	criteria provided, single submitter	clinical testing	Reported in many patients with familial dysalbuminemic hyperthyroxinemia (Petersen et al., 1994; Choudhary et al., 2015; Cho et al., 2017; Khoo et al., 2020); Also reported as R218H due to alternate nomenclature; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26522458, 30027432, 9329347, 11743520, 27834068, 24646103, 24494774, 8048949, 12743361, 19723509, 25153218, 28781323, 26169058, 29676214, 32101523, 30197844, 29133890, 8064810, 12099390)
Invitae	RCV001753423	SCV003251568	uncertain significance	not provided	2023-01-22	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects ALB function (PMID: 12743361). 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) performed at Invitae indicates that this missense variant is not expected to disrupt ALB protein function. ClinVar contains an entry for this variant (Variation ID: 18225). This variant is also known as R218H. This missense change has been observed in individual(s) with dysalbuminemic hyperthyroxinemia (PMID: 8048949, 12099390, 26169058, 29676214, 33728390). This variant is present in population databases (rs75002628, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 242 of the ALB protein (p.Arg242His).
3billion	RCV000019886	SCV004013589	uncertain significance	Hyperthyroxinemia, familial dysalbuminemic		criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ALB related disorder (Also known as Arg218His. PMID: 8048949). Different missense changes at the same codon (p.Arg242Pro, p.Arg242Ser) have been reported to be associated with ALB related disorder (ClinVar ID: VCV000018238 / PMID: 24494774, 9329347). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as Uncertain significance according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398549	SCV004122526	uncertain significance	not specified	2023-10-05	criteria provided, single submitter	clinical testing	Variant summary: ALB c.725G>A (p.Arg242His) results in a non-conservative amino acid change located in the Serum albumin, N-terminal (IPR014760) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251392 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALB causing Analbuminemia (7.2e-05 vs ND), allowing no conclusion about variant significance. c.725G>A has been reported in the literature in individuals affected with Dysalbuminaemic hyperthyroxinaemia (e.g. Cho_2017, Ryan_2016, Sunthornthepvarakul_1994, Petersen_1994) . These reports do not provide unequivocal conclusions about association of the variant with Analbuminemia. 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: 27834068, 8064810, 26169058, 8048949). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
OMIM	RCV000019886	SCV000040184	pathogenic	Hyperthyroxinemia, familial dysalbuminemic	2001-12-01	no assertion criteria provided	literature only