Submissions for variant NM_000155.4(GALT):c.290A>G (p.Asn97Ser)

dbSNP: rs111033669

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723577	SCV000110055	pathogenic	not provided	2013-01-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022077	SCV000934199	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 97 of the GALT protein (p.Asn97Ser). This variant is present in population databases (rs111033669, gnomAD 0.0009%). This missense change has been observed in individual(s) with classic galactosemia (PMID: 7550229, 15633893). This variant is also known as 318A>G. ClinVar contains an entry for this variant (Variation ID: 25146). 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 with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Asn97 amino acid residue in GALT. Other variant(s) that disrupt this residue have been observed in individuals with GALT-related conditions (PMID: 22944367), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022077	SCV001363672	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2019-09-06	criteria provided, single submitter	clinical testing	Variant summary: GALT c.290A>G (p.Asn97Ser, legacy name c.318A>G) results in a conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain (IPR005849) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Five predict the variant creates a cryptic 3 acceptor site. A functional study, Ashino_1995 found the variant supports these predictions. The variant allele was found at a frequency of 4e-06 in 251494 control chromosomes (gnomAD). c.290A>G has been reported in the literature in individuals affected with Galactosemia (eg. Ashino_1995, Shin_2004, Waisbren_2012). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (eg. Ashino_1995). A ClinVar submission (evaluation after 2014) cites the variant as likely pathogenic. Furthermore, another variant affecting the same codon, N97D, and nearby codons, F95L, D98N, D98H, have been reported in association with Galactosaemia (via HGMD). Therefore, suggesting this region is important for GALT protein function. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000022077	SCV003834115	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2022-03-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000022077	SCV004198525	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-07-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004730853	SCV005337567	pathogenic	GALT-related disorder	2024-05-10	no assertion criteria provided	clinical testing	The GALT c.290A>G variant is predicted to result in the amino acid substitution p.Asn97Ser. This variant, also referred to as c.318A>G using legacy nomenclature, has been reported in the homozygous and compound heterozygous states in multiple individuals with galactosemia (see for example, Table 1, Ashino et al. 1995. PubMed ID: 7550229; Table 3, Shin and Podskarbi. 2004. PubMed ID: 15633893; Table 2, Waisbren et al. 2011. PubMed ID: 21779791). An RT-PCR study suggests this variant impacts mRNA splicing via using of a cryptic splice acceptor site and leads to a frameshift loss-of-function effect (Figure 2, Ashino et al. 1995. PubMed ID: 7550229). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.