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

gnomAD frequency: 0.00003  dbSNP: rs111033670

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723399	SCV000228799	pathogenic	not provided	2018-07-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022079	SCV000833544	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 98 of the GALT protein (p.Asp98Asn). This variant is present in population databases (rs111033670, gnomAD 0.006%). This missense change has been observed in individual(s) with galactosemia (PMID: 10408771, 12595586, 17876724, 22743281). ClinVar contains an entry for this variant (Variation ID: 25148). 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 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000022079	SCV002053954	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase		criteria provided, single submitter	research
Myriad Genetics, Inc.	RCV000022079	SCV002060382	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2021-10-22	criteria provided, single submitter	clinical testing	NM_000155.3(GALT):c.292G>A(D98N) is a missense variant classified as likely pathogenic in the context of galactosemia. D98N has been observed in cases with relevant disease (PMID: 31358168, 28644047, 17876724, 27363831, 30718057, 12595586). Functional assessments of this variant are not available in the literature. D98N has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000155.3(GALT):c.292G>A(D98N) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000022079	SCV002506308	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2022-09-23	criteria provided, single submitter	clinical testing	The GALT c.292G>A; p.Asp98Asn variant (rs111033670), is reported in the compound heterozygous state in the literature in individuals affected with galactosemia (Calderon 2007, Tyfield 1999). This variant is reported in ClinVar (Variation ID: 25148), and found in the general population with an overall allele frequency of 0.003% (10/282870 alleles) in the Genome Aggregation Database. The aspartate at codon 98 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.954). Based on available information, this variant is considered to be pathogenic. References: Calderon FR et al. Combination of enzyme analysis, allele-specific PCR and sequencing to detect mutations in the GALT gene. J Inherit Metab Dis. 2007 Oct;30(5):818. PMID: 17876724. Tyfield L et al. Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Hum Mutat. 1999;13(6):417-30. PMID: 10408771
Fulgent Genetics, Fulgent Genetics	RCV000022079	SCV002809731	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2021-07-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000022079	SCV004198492	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-03-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000723399	SCV005325868	pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28644047, 10408771, 17876724, 22743281, 20008339, 27363831, 31358168, 30718057, 34302356, 12595586)
Natera, Inc.	RCV001826490	SCV002085195	pathogenic	Galactosemia	2017-03-16	no assertion criteria provided	clinical testing