ClinVar Miner

Submissions for variant NM_013339.4(ALG6):c.257+5G>A (rs199682486)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Miraca Genetics Laboratories, RCV000192479 SCV000328845 pathogenic Congenital disorder of glycosylation type 1C 2016-05-01 no assertion criteria provided clinical testing Our laboratory reported dual molecular diagnoses in ALG6 (NM_013339.3:c.257+5G>A; NM_013339.3:c.988G>T; in trans) and SHOX (NM_000451.3:c.517C>T) in an individual with mild hypotonia, poor feeding, congenital heart disease (VSD, PFO, PDA), seizure disorder, dysmorphic facies, small chest wall, bowed lower legs, apparently short upper extremities, shallow sacral dimple, small for gestational age and a history of prematurity and intrauterine growth restriction.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000081557 SCV000511796 pathogenic not provided 2016-09-16 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000192479 SCV000745454 pathogenic Congenital disorder of glycosylation type 1C 2015-09-21 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000192479 SCV000734047 pathogenic Congenital disorder of glycosylation type 1C no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081557 SCV000113488 pathogenic not provided 2013-06-28 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000192479 SCV000611248 pathogenic Congenital disorder of glycosylation type 1C 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000081557 SCV000568303 pathogenic not provided 2018-04-09 criteria provided, single submitter clinical testing The c.257+5G>A variant in the ALG6 gene is one of the most common variants in the ALG6 gene and has been identified previously in both the homozygous and compound heterozygous states in multiple unrelated individuals with ALG6-CDG (Imbach et al., 2000; Drijvers et al., 2010; Dercksen et al., 2013; Morava et al., 2016). This variant is predicted to destroy the splice donor site in intron 4, and is expected to cause abnormal gene splicing. Functional studies indicate that c.257+5G>A (reported using alternate nomenclature IVS3+5G>A) transfected cells produce a nonfunctional enzyme that is unable to restore normal glycosylation in a yeast strain lacking functional ALG6 (Westphal et al., 2000). The c.257+5G>A variant is observed in 119/126470 (0.094%) alleles from individuals of non-Finnish European background in large population cohorts, but was not seen in the homozygous state (Lek et al., 2016). In summary, we interpret c.257+5G>A as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000192479 SCV000246350 pathogenic Congenital disorder of glycosylation type 1C 2015-07-22 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000192479 SCV000743997 pathogenic Congenital disorder of glycosylation type 1C 2017-07-28 criteria provided, single submitter clinical testing
Invitae RCV000192479 SCV000824414 pathogenic Congenital disorder of glycosylation type 1C 2019-01-09 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the ALG6 gene. It does not directly change the encoded amino acid sequence of the ALG6 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs199682486, ExAC 0.08%). This variant has been reported in the compound heterozygous state in multiple individuals affected with congenital disorder of glycosylation 1c (PMID: 10924277, 23430515, 10914684, 20447155). This variant is also known as IVS3+5G>A. ClinVar contains an entry for this variant (Variation ID: 95529). Experimental studies have shown that this intronic change causes the in-frame skipping of exon 3, which produces a nonfunctional enzyme (PMID: 10924277). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000192479 SCV000538013 pathogenic Congenital disorder of glycosylation type 1C 2016-03-30 criteria provided, single submitter clinical testing The c.257+5G>A splicing variant in the ALG6 gene has been previously reported in individuals affected with autosomal recessive congenital disorder of glycosylation Ic, and in trans with a known pathogenic variant (Imbach et al. 2000 and Westphal et al. 2000). This variant is shown to cause the skipping of exon 3, and produces a nonfunctional enzyme as shown by its inability to restore normal glycosylation in a yeast strain lacking a functional ALG6 (Westphal et al. 2000). This c.257+5G>A has been reported in very low frequency in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAc) and has been reported pathogenic in the Emory Genetic Patient Database. Therefore, this collective evidence supports the classification of the c.257+5G>A as a recessive pathogenic variant for congenital disorder of glycosylation type Ic.

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