ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.290A>G (p.Asn97Ser) (rs111033669)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723577 SCV000110055 pathogenic not provided 2013-01-17 criteria provided, single submitter clinical testing
Invitae RCV000022077 SCV000934199 likely pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2018-09-24 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 97 of the GALT protein (p.Asn97Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs111033669, ExAC 0.001%). This variant has been observed in individuals affected with classic galactosemia (PMID: 7550229, 15633893). It is also known as 318A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 25146). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A study of RNA derived from an affected individual has shown that this missense change results in the creation of a cryptic splice site that, when utilized, results in a frameshift (PMID: 7550229). This variant disrupts the p.Asn97 amino acid residue in GALT. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 22944367), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
Integrated Genetics/Laboratory Corporation of America 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.
Research and Development, ARUP Laboratories RCV000022077 SCV000042753 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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