Submissions for variant NM_000155.4(GALT):c.619C>T (p.Gln207Ter) (rs111033743)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Integrated Genetics/Laboratory Corporation of America	RCV000022166	SCV000695697	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2019-03-25	criteria provided, single submitter	clinical testing	Variant summary: GALT c.619C>T (p.Gln207X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.947G>A, p.Trp316X). The variant allele was found at a frequency of 1.6e-05 in 251584 control chromosomes (gnomAD and publication data). c.619C>T has been reported in the literature in two unrelated individuals affected with Galactosemia, where one patient was carrying it in the homozygous state (Yang 2002, Carney 2009). These patients also carried a milder mutation (Duarte-2 allele) in homozygous state. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000723401	SCV000700295	pathogenic	not provided	2016-10-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000022166	SCV000791700	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2017-05-26	criteria provided, single submitter	clinical testing
Invitae	RCV000022166	SCV001233763	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2019-06-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln207*) in the GALT gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with galactosemia (PMID: 11754113, 19224951). ClinVar contains an entry for this variant (Variation ID: 25230). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in GALT are known to be pathogenic (PMID: 22944367). For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories	RCV000022166	SCV000042848	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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