ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.691C>T (p.Arg231Cys) (rs111033749)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185919 SCV000238872 pathogenic not provided 2016-11-29 criteria provided, single submitter clinical testing The R231C missense mutation in the GALT gene has been reported previously in association with galactosemia (Boutron et al., 2012). The variant is found in GALT panel(s).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000185919 SCV000340775 pathogenic not provided 2018-02-15 criteria provided, single submitter clinical testing
Counsyl RCV000022184 SCV000486527 likely pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2016-06-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000022184 SCV000695700 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2016-11-14 criteria provided, single submitter clinical testing Variant summary: The GALT c.691C>T (p.Arg231Cys) variant involves the alteration of a conserved nucleotide and is located in the intersubunit interface of the protein (Boutron_2012). 4/4 in silico tools predict a damaging outcome for this variant. This variant has been reported multiple patients with galactosemia in homozygous or compound heterozygous state with other pathogenic variants (Alfadhel_2016, Boutron_2012, Schadewaldt_2003) and is absent in 121210 control chromosomes. A functional study showed this variant leads to loss of enzymatic activity (Coelho_2014). Another missense change (p.R231H) at this residue has also been reported in association with galactosemia (ARUP, ClinVar). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae RCV000022184 SCV000820402 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 231 of the GALT protein (p.Arg231Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with low GALT enzyme activity, findings that are highly specific for galactose-1-phosphate uridylyltransferase deficiency (PMID: 14518827, 22944367, Invitae). ClinVar contains an entry for this variant (Variation ID: 25246). Experimental studies have shown that this missense change results in a GALT protein with reduced enzyme activity (PMID: 25814382, 25614870). A different missense substitution at this codon (p.Arg231His) has been determined to be pathogenic (PMID: 22944367, 25614870, 7550229, 11152465). This suggests that the arginine residue is critical for GALT protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories RCV000022184 SCV000042866 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.

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