ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.292G>A (p.Asp98Asn) (rs111033670)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000022079 SCV000795894 likely pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2017-11-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723399 SCV000228799 pathogenic not provided 2018-07-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000022079 SCV000917410 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2017-11-16 criteria provided, single submitter clinical testing Variant summary: The GALT c.292G>A (p.Asp98Asn) variant involves the alteration of a conserved nucleotide, is located in UDP-alpha-D-glucose binding region and is involved in interaction with substrate (UniProt, Facchiano_2010). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 8/277204 control chromosomes (gnomAD) at a frequency of 0.0000289, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALT variant (0.0028868). This variant has been reported in multiple patients with galactosemia in homozygous as well as in compound heterozygous state with other pathogenic variants (Tyfield, Webb_2003, Schulpis_2017, ARUP). Enzymatic analysis of the homozygote showed no activity, strongly suggesting that this variant is defective. Another missense change at the same codon (p.Asp98His) has been classified as pathogenic by our lab, suggesting functional importance of this codon. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000022079 SCV000833544 likely pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2018-02-23 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 98 of the GALT protein (p.Asp98Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs111033670, ExAC 0.001%). This variant has been observed in the homozygous or compound heterozygous state in individuals affected with galactosemia (PMID: 12595586, 10408771, 22743281). ClinVar contains an entry for this variant (Variation ID: 25148). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Research and Development, ARUP Laboratories RCV000022079 SCV000042755 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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