Submissions for variant NM_000155.4(GALT):c.292G>C (p.Asp98His) (rs111033670)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000790788	SCV000330952	pathogenic	not provided	2015-11-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022080	SCV000695687	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2016-08-10	criteria provided, single submitter	clinical testing	Variant summary: The GALT c.292G>C (p.Asp98His) variant involves the alteration of a non-conserved nucleotide. The altered amino acid Asp98 is located in Galactose-1-phosphate uridyl transferase, N-terminal dormain and HIT-like domain. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121426 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALT variant (0.0028868). It was reported in patients with hereditary galactosemia and proven reduced enzyme activity (less than 10% of the WT enzyme) suggesting pathogenicity. Moreover, another variant affecting the same residue, p.Asp98Asn has been reported to be associated with galactosemia indicating the variant to be located in a mutational hotspot and the clinical importance of the Asp98 residue. In addition, a clinical diagnostic laboratory classified the variant as pathogenic via ClinVar. Taken together, this variant is classified as pathogenic.
Invitae	RCV000022080	SCV000755879	uncertain significance	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2017-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with histidine at codon 98 of the GALT protein (p.Asp98His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs111033670, ExAC no frequency). This variant has not been reported in the literature in individuals with GALT-related disease. ClinVar contains an entry for this variant (Variation ID: 25149). 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"). A different missense substitution at this codon (p.Asp98Asn) has been determined to be pathogenic (PMID: 12595586, 10408771, 22743281). This suggests that the aspartic acid residue is critical for GALT protein function and that other missense substitutions at this position may also be pathogenic. 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	RCV000022080	SCV001163232	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase		criteria provided, single submitter	clinical testing
Research and Development, ARUP Laboratories	RCV000022080	SCV000042756	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2012-12-04	no assertion criteria provided	clinical testing	Converted during submission to Pathogenic.
Counsyl	RCV000022080	SCV001132395	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2018-10-02	no assertion criteria provided	clinical testing