ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.982C>T (p.Arg328Cys) (rs144993986)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000431337 SCV000521167 likely pathogenic not provided 2016-11-16 criteria provided, single submitter clinical testing The R328C missense change in the GALT gene has been reported previously in a patient with classic galactosemia who was compound heterozygous for R328C and the Q188R pathogenic variant (Forges et al. 2011). The R328C variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R328C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a missense variant at the same residue (R328H) and missense variants in nearby residues (Y323D, P324S/L, L327P, S329F, A330V, R333G/W/L/Q) have been reported in the Human Gene Mutation Database in association with galactosemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we interpret R328C to be likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589987 SCV000695711 likely pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2016-08-30 criteria provided, single submitter clinical testing Variant summary: The GALT c.982C>T (p.Arg328Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). Arg328 is highly conserved across species and is located at the intersubunit interface and could potentially perturb the correct dimeric association of the GALT enzyme (Boutron 2012). Additionally, it affects the same codon as the previously reported c.983G>A (p.Arg328His; PubMed: 10408771 and 20008339). The variant of interest was found in 2/121406 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALT variant (0.0028868). It has been reported in one patient with severe GALT who was compound heterozygous with the common pathogenic GALT variant, p.Q188R. This patient had an undetectable GALT activity (Forges 2011). Taken together, this variant is classified as likely pathogenic.
Invitae RCV000589987 SCV000827413 uncertain significance Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 328 of the GALT protein (p.Arg328Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs144993986, ExAC 0.01%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with galactosemia (PMID: 20663501). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 381664). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Baylor Genetics RCV000589987 SCV001163250 likely pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase criteria provided, single submitter clinical testing

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