Submissions for variant NM_013339.4(ALG6):c.908_910del (p.Cys303del)

dbSNP: rs1057517952

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000412711	SCV000491165	likely pathogenic	not provided	2016-09-23	criteria provided, single submitter	clinical testing	The c.908_910delGTT variant in the ALG6 gene has been previously reported in an least one individual with CDG who had a second variant, c.257+5G>A, although the phase for these two variants is unknown (Morava et al., 2016). The c.908_910delGTT variant causes an in-frame deletion of one amino acid, Cysteine 303, denoted p.C303del. This amino acid deletion occurs at a position that is not conserved across species. However, the c.908_910delGTT was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.908_910delGTT as a likely pathogenic variant.
Genetic Services Laboratory, University of Chicago	RCV000504484	SCV000593108	uncertain significance	not specified	2015-11-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000504484	SCV002500605	uncertain significance	not specified	2022-03-23	criteria provided, single submitter	clinical testing	Variant summary: ALG6 c.908_910delGTT (p.Cys303del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 249388 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.908_910delGTT has been reported in the literature as a presumed compound heterozygous genotype in at-least one individual affected with alpha-1,3-glucosyltransferase congenital disorder of glycosylation (ALG6-CDG) (example, Morava_2016) and also listed without a second allele or zygosity specified in a mutational update report (example, Haeuptle_2009). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.