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

gnomAD frequency: 0.00083  dbSNP: rs80338851

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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	2022-01-06	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; leads to skipping of exon 8, as confirmed by RT-PCR studies (Lesnik Oberstein et al., 2006); Also known as c.1020+1G>A using alternate nomenclature; This variant is associated with the following publications: (PMID: 26684045, 25525159, 19796186, 29096039, 18798333, 16909395, 23161355, 34426522, 31589614, 30577886, 31081795, 32224865, 31795264, 32204707, 33726816, 32732226)
Illumina Laboratory Services, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000001326	SCV000759969	pathogenic	Peters plus syndrome	2023-12-22	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. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (rs80338851, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individuals with Peters-Plus syndrome (PMID: 16909395, 18199743, 19796186, 23161355, 23213277, 23889335, 26684045). 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. 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 Center for Human Genetics Tuebingen	RCV000082789	SCV001500571	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	B3GLCT: PVS1, PM2
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000082789	SCV002010931	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
3billion	RCV000001326	SCV002521159	pathogenic	Peters plus syndrome	2022-05-22	criteria provided, single submitter	clinical testing	Substitution at the splicing junction produces an abnormal splicing effect, which is expected to cause a loss of normal protein function via nonsense-mediated mRNA decay. This variant has been reported as pathogenic more than twice (ClinVar ID: VCV000001264), along with assertion criteria based on the ACMG guidelines. It has been reported with an extremely low frequency in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001326	SCV002547796	pathogenic	Peters plus syndrome	2022-04-18	criteria provided, single submitter	clinical testing	Variant summary: B3GALTL c.660+1G>A (aka c.1020+1G>A) is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. The variant allele was found at a frequency of 0.00076 in 281510 control chromosomes (gnomAD). The variant, c.660+1G>A, has been reported in the literature in numerous homozygous- and compound heterozygous individuals affected with Peters Plus Syndrome (see e.g. Lesnik_2006, Hess_2008, Wang_2020); the variant was described as a recurrent mutation in many different ethnicities, and was reported as the most frequent disease associated allele. These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence and confirmed that the variant results in the skipping of exon 8, in addition, fucosylation defects were also demonstrated in patients (Lesnik_2006, Hess_2008). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000001326	SCV002556402	pathogenic	Peters plus syndrome	2021-12-13	criteria provided, single submitter	clinical testing	The B3GLCT c.660+1G>A variant is classified as PATHOGENIC (PS4, PVS1) The B3GLCT c.660+1G>A variant is located in a splice donor region (PVS1). This recurrent variant has been identiified in both a homozygous and comound heterozygous state in multiple individuals with Peters-plus syndrome (PMID:16909395) (PS4). This variant is in dbSNP (rs80338851) and has been reported in population databases (gnomAD 122/152076 alleles, no homozygotes). This variant has been reported in ClinVar as pathogenic by other diagnostic laboratories (Variation ID:1264) and is damaging in HGMD for Peters-plus syndrome (CS064369).
MGZ Medical Genetics Center	RCV000001326	SCV002579682	pathogenic	Peters plus syndrome	2022-03-08	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000001326	SCV002587024	pathogenic	Peters plus syndrome	2021-09-28	criteria provided, single submitter	research
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000001326	SCV003807659	pathogenic	Peters plus syndrome	2023-01-23	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 strong, PM3 strong
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000001326	SCV003932257	pathogenic	Peters plus syndrome	2023-01-25	criteria provided, single submitter	clinical testing	PVS1, PM3_strong
Baylor Genetics	RCV000001326	SCV004041470	pathogenic	Peters plus syndrome	2023-01-06	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	not provided	Peters plus syndrome		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000082789	SCV001739941	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000082789	SCV001798532	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000082789	SCV001927667	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000082789	SCV001973416	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000001326	SCV002583408	pathogenic	Peters plus syndrome	2022-03-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398411	SCV004104109	pathogenic	B3GLCT-related disorder	2024-08-04	no assertion criteria provided	clinical testing	The B3GLCT c.660+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported to be a common pathogenic variant for Peters Plus syndrome in the homozygous or compound heterozygous state (described as c.1020+1 G>A, Lesnik Oberstein. 2006. PubMed ID: 16909395; Reis., 2008. PubMed ID: 18798333). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in B3GLCT are expected to be pathogenic. This variant is interpreted as pathogenic.