ClinVar Miner

Submissions for variant NM_194318.4(B3GLCT):c.660+1G>A (rs80338851)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000082789 SCV000232806 pathogenic not provided 2014-12-10 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000082789 SCV000280698 pathogenic not provided 2014-11-14 criteria provided, single submitter clinical testing
GeneDx RCV000082789 SCV000329095 pathogenic not provided 2018-05-08 criteria provided, single submitter clinical testing The c.660+1G>A pathogenic variant is one of the most common variants reported in the B3GLCT gene and has been reported as c.1020+1G>A due to alternate nomenclature in the homozygous and compound heterozygous states in association with Peters plus syndrome (Lesnik Oberstein et al., 2006; Reis et al., 2008). In addition, in a study of 44 fetuses with prenatally diagnosed hydrocephaly, four of the fetuses also presenting with cleft lip/palate, agenesis of the corpus callosum, hypertelorism, eye anomalies, and brachydactyly were found to harbor the c.660+1G>A variant in the homozygous state (Schoner et al., 2013). This splice site variant destroys the canonical splice donor site in intron 8 and leads to skipping of exon 8, as confirmed by RT-PCR studies (Lesnik Oberstein et al., 2006). The c.660+1G>A variant is observed in 154/126,284 (0.12%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). We interpret c.660+1G>A as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000001326 SCV000383588 pathogenic Peters plus syndrome 2017-04-27 criteria provided, single submitter clinical testing The B3GALTL c.660+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.660+1G>A variant is well described in the literature and is the most frequently identified variant in individuals with Peters plus syndrome (PPS) (Saskia et al. 2014). Across a selection of literature, the c.660+1G>A variant was reported in a homozygous state in 24 patients and in a compound heterozygous state in 13 patients (Lesnik Oberstein et al. 2006; Reis et al. 2008; Dassie-Ajdid et al. 2009; Schoner et al. 2013; Weh et al. 2013). Parental testing was described in at least 15 sets of parent of affected patients, and the c.660+1G>A variant was identified in unaffected parents as expected based on their child's genotype. Hess et al.(2008) demonstrated that synthesis of the disaccharide Glc-β1,3-Fuc-O- is disrupted in patients with homozygous B3GALTL variants in contrast with their heterozygous relatives. The c.660+1G>A variant was not detected in 455 control chromosomes and is reported at a frequency of is 0.00104 in the non-Finnish European population of the Exome Aggregation Consortium. Based on the collective evidence and the potential impact of splice donor variants the c.660+1G>A variant is classified as pathogenic for Peters plus syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000001326 SCV000759969 pathogenic Peters plus syndrome 2020-09-08 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 of the B3GLCT gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs80338851, ExAC 0.1%). This variant is the most common cause of Peters-plus syndrome, accounting for the majority of the alleles reported (PMID: 16909395, 18199743, 19796186, 23161355, 23213277, 23889335, 26684045). This variant is also known as c.1020+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 1264). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in B3GLCT are known to be pathogenic (PMID: 18798333, 23889335). For these reasons, this variant has been classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000001326 SCV000803795 pathogenic Peters plus syndrome 2016-04-12 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000001326 SCV001369876 pathogenic Peters plus syndrome 2018-10-12 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2,PP3.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000001326 SCV001448829 pathogenic Peters plus syndrome 2017-11-10 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000082789 SCV001500571 pathogenic not provided 2020-10-01 criteria provided, single submitter clinical testing
OMIM RCV000001326 SCV000021476 pathogenic Peters plus syndrome 2009-11-01 no assertion criteria provided literature only
GeneReviews RCV000001326 SCV000041737 pathologic Peters plus syndrome 2011-02-17 no assertion criteria provided curation Converted during submission to Pathogenic.

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