Submissions for variant NM_000155.4(GALT):c.590A>G (p.Asp197Gly)

gnomAD frequency: 0.00001  dbSNP: rs1554709359

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671944	SCV000796988	uncertain significance	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2018-01-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000671944	SCV002247896	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-05-02	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 expected to disrupt GALT protein function. ClinVar contains an entry for this variant (Variation ID: 556007). This missense change has been observed in individual(s) with clinical features of galactosemia (PMID: 22743281, 28065439). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 197 of the GALT protein (p.Asp197Gly).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702301	SCV005204292	uncertain significance	not specified	2024-06-13	criteria provided, single submitter	clinical testing	Variant summary: GALT c.590A>G (p.Asp197Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251486 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.590A>G has been reported in the literature in individuals affected with clinical features of Galactosemia (Liu_2012, Welling_2017). These data do not allow any conclusion about variant significance. 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: 22743281, 28065439). ClinVar contains an entry for this variant (Variation ID: 556007). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004752989	SCV005359445	likely pathogenic	GALT-related disorder	2024-09-18	no assertion criteria provided	clinical testing	The GALT c.590A>G variant is predicted to result in the amino acid substitution p.Asp197Gly. This variant has been reported in the compound heterozygous state in an individual with atypical classic galactosemia as identified by a positive newborn metabolic screen (Welling et al. 2017. PubMed ID: 28065439). This individual was found to have GALT protein activity of 3.6% compared to normal (Welling et al. 2017. PubMed ID: 28065439). This variant was also identified along with a known pathogenic GALT variant (p.Gln188Arg) in an individual with a confirmed diagnosis of galactosemia (P8 in Liu et al. 2012. PubMed ID: 22743281). This variant has not been reported in a large population database, indicating this variant is rare. Given the evidence, we interpret c.590A>G (p.Asp197Gly) as likely pathogenic.