Submissions for variant NM_000155.4(GALT):c.687+9G>C

gnomAD frequency: 0.00057  dbSNP: rs117998880

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000871944	SCV000479764	uncertain significance	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588651	SCV000695699	likely benign	not specified	2020-07-20	criteria provided, single submitter	clinical testing	Variant summary: GALT c.687+9G>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00072 in 251404 control chromosomes, including one homozygote, predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in GALT causing Galactosemia (0.00072 vs 0.0029), allowing no conclusion about variant significance, however the presence of a homozygous individual in the gnomAD database suggests that the variant may be benign. To our knowledge, no occurrence of c.687+9G>C in individuals affected with Galactosemia and no experimental evidence demonstrating its impact on protein function have been reported in the literature. Co-occurrences with other pathogenic variants (GALT c.-119_-116delGTCA; GALT c.[-1039_753del3162; 820+51_*789del2294ins12]) have been reported in unaffected individuals undergoing carrier screening (internal database), providing supporting evidence for a benign role. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as likely benign, and one laboratory cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000871944	SCV001013686	likely benign	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2025-02-03	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001276331	SCV001462503	uncertain significance	Galactosemia	2018-05-22	no assertion criteria provided	clinical testing