Submissions for variant NM_000155.4(GALT):c.91C>A (p.His31Asn)

dbSNP: rs111033643

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000585998	SCV000695709	uncertain significance	not provided	2016-09-09	criteria provided, single submitter	clinical testing	Variant summary: The GALT c.91C>A (p.His31Asn) variant involves the alteration of a conserved nucleotide. His31 is highly conserved across species and is located in the Galactose-1-phosphate uridyl transferase, N-terminal domain and histidine triad motif (HIT)-like domain. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was absent in 121362 control chromosomes. One clinical diagnostic laboratory classified this variant as pathogenic without providing evidence. Another missense change at this same position, p.H31R, has been reported as pathogenic (via HGMD) in a galactosemia patient reported in the literature (PMID: 20547145), suggesting H31 is critical for the normal function of GALT protein and that it is a mutational hot spot. However, only one patient has been identified to carry this variant and no functional study was available at the time of variant classification. Taken together, this variant is classified as VUS-possibly pathogenic until additional patients and/or functional studies are available.
Invitae	RCV003502508	SCV004294291	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-05-23	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 25122). 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. This missense change has been observed in individual(s) with classic galactosemia (PMID: 22944367). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 31 of the GALT protein (p.His31Asn).
Natera, Inc.	RCV001826488	SCV002085182	uncertain significance	Galactosemia	2020-09-28	no assertion criteria provided	clinical testing