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

gnomAD frequency: 0.00065  dbSNP: rs199682486

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081557	SCV000113488	pathogenic	not provided	2013-06-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000192479	SCV000246350	pathogenic	ALG6-congenital disorder of glycosylation 1C	2015-07-22	criteria provided, single submitter	clinical testing
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
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000192479	SCV000538013	pathogenic	ALG6-congenital disorder of glycosylation 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.
GeneDx	RCV000081557	SCV000568303	pathogenic	not provided	2023-08-31	criteria provided, single submitter	clinical testing	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); Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 21541726, 23430515, 20447155, 10914684, 27959697, 10924277, 27287710, 31980526, 31589614, 35279850, 36756224)
Fulgent Genetics, Fulgent Genetics	RCV000192479	SCV000611248	pathogenic	ALG6-congenital disorder of glycosylation 1C	2022-03-15	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000192479	SCV000743997	pathogenic	ALG6-congenital disorder of glycosylation 1C	2017-07-28	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000192479	SCV000745454	pathogenic	ALG6-congenital disorder of glycosylation 1C	2015-09-21	criteria provided, single submitter	clinical testing
Invitae	RCV000192479	SCV000824414	pathogenic	ALG6-congenital disorder of glycosylation 1C	2024-01-27	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. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs199682486, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with congenital disorder of glycosylation 1c (PMID: 10914684, 10924277, 20447155, 23430515). This variant is also known as IVS3+5G>A. ClinVar contains an entry for this variant (Variation ID: 95529). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 10924277). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000192479	SCV001194124	likely pathogenic	ALG6-congenital disorder of glycosylation 1C	2021-10-01	criteria provided, single submitter	clinical testing	NM_013339.3(ALG6):c.257+5G>A is an intronic variant classified as likely pathogenic in the context of congenital disorder of glycosylation type Ic. c.257+5G>A has been observed in cases with relevant disease (PMID: 27287710, 27959697). Functional assessments of this variant are available in the literature (PMID: 10924277, 10914684). c.257+5G>A has been observed in population frequency databases (gnomAD: NFE 0.09%). In summary, NM_013339.3(ALG6):c.257+5G>A is an intronic variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.​
Revvity Omics, Revvity	RCV000192479	SCV002021348	likely pathogenic	ALG6-congenital disorder of glycosylation 1C	2021-02-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000192479	SCV003844924	pathogenic	ALG6-congenital disorder of glycosylation 1C	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: ALG6 c.257+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing, including three that predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in a skipping of exon 3 (Imbach_2000). The variant allele was found at a frequency of 0.00047 in 250774 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALG6 causing Congenital Disorder Of Glycosylation Type 1C (0.00047 vs 0.0011), allowing no conclusion about variant significance. c.257+5G>A has been reported in the literature in multiple compound heterozygous individuals affected with Congenital Disorder Of Glycosylation (Abu Bakkar_2022, Imbach_2000, Morava_2016, Westphal_2000), some of whom were reported to have other (likely) pathogenic variants of ALG6 in trans. These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating the effect of transforming ALG6 missing exon 3 in an alg6-deficient strain of S. cerevisiae, finding that it is unable restore glycosylation activity (Westphal_2000). 12 submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000192479	SCV003921990	pathogenic	ALG6-congenital disorder of glycosylation 1C	2021-05-07	criteria provided, single submitter	clinical testing	0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation, type Ic (MIM#603147). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been proven to cause in-frame skipping of exon 3 (PMID: 10924277). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (103 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in multiple patients with congenital disorder of glycosylation, type Ic (ClinVar, PMID: 10924277). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV000192479	SCV000328845	pathogenic	ALG6-congenital disorder of glycosylation 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000192479	SCV000734047	pathogenic	ALG6-congenital disorder of glycosylation 1C		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000192479	SCV001456276	pathogenic	ALG6-congenital disorder of glycosylation 1C	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000081557	SCV001808132	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000081557	SCV001951808	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000081557	SCV002036640	likely pathogenic	not provided		no assertion criteria provided	clinical testing