rs80338851

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_194318.4(B3GLCT):c.660+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,588,686 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 0 hom. )

Consequence

B3GLCT
NM_194318.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:26O:1

Conservation

PhyloP100: 8.71

Variant links:

Genes affected

B3GLCT (HGNC:20207): (beta 3-glucosyltransferase) The protein encoded by this gene is a beta-1,3-glucosyltransferase that transfers glucose to O-linked fucosylglycans on thrombospondin type-1 repeats (TSRs) of several proteins. The encoded protein is a type II membrane protein. Defects in this gene are a cause of Peters-plus syndrome (PPS).[provided by RefSeq, Mar 2009]

B3GLCT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-31269278-G-A is Pathogenic according to our data. Variant chr13-31269278-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-31269278-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B3GLCT	NM_194318.4 link	c.660+1G>A		splice_donor_variant, intron_variant	Intron 8 of 14	ENST00000343307.5	NP_919299.3	Q6Y288

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B3GLCT	ENST00000343307.5 link	c.660+1G>A		splice_donor_variant, intron_variant	Intron 8 of 14	1	NM_194318.4	ENSP00000343002.4		Q6Y288
B3GLCT	ENST00000461652.2 link	n.275+1G>A		splice_donor_variant, intron_variant	Intron 3 of 6	3

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00141

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000700

AC:

175

AN:

250126

Hom.:

AF XY:

0.000688

AC XY:

AN XY:

135206

show subpopulations

Gnomad AFR exome

AF:

0.000249

Gnomad AMR exome

AF:

0.000754

Gnomad ASJ exome

AF:

0.000699

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.000281

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.000819

GnomAD4 exome

AF:

0.00106

AC:

1521

AN:

1436492

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

721

AN XY:

716300

show subpopulations

Gnomad4 AFR exome

AF:

0.000212

Gnomad4 AMR exome

AF:

0.000717

Gnomad4 ASJ exome

AF:

0.000732

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000140

Gnomad4 FIN exome

AF:

0.000717

Gnomad4 NFE exome

AF:

0.00125

Gnomad4 OTH exome

AF:

0.000805

GnomAD4 genome

AF:

0.000802

AC:

122

AN:

152194

Hom.:

Cov.:

AF XY:

0.000632

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000472

Gnomad4 NFE

AF:

0.00141

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000983

Hom.:

Bravo

AF:

0.000831

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00169

EpiControl

AF:

0.00113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peters plus syndrome

Pathogenic:15Other:1

Mar 01, 2022

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 06, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 25, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM3_strong -

Oct 12, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2,PP3. -

Apr 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Sep 28, 2021

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 13, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17981815, 18413255, 23093928). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.98 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.97 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013351 /PMID: 16439621 /3billion dataset). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 16439621, 17551924, 18042262). Different missense changes at the same codon (p.Tyr130Asn, p.Tyr130His) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040747, VCV000636238 /PMID: 18413255, 19156172). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 23, 2023

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 strong, PM3 strong -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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-Î²1,3-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. -

Mar 08, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2017

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 13, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Apr 12, 2016

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

not provided

Pathogenic:9

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 10, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 14, 2014

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

B3GLCT: PVS1, PM2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

B3GLCT-related disorder

Pathogenic:1

Aug 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Inborn genetic diseases

Pathogenic:1

Oct 18, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.660+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 8 of the B3GLCT gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of 0.076% (214/281510) total alleles studied. The highest observed frequency was 0.122% (157/128666) of European (non-Finnish) alleles. This alteration is the most common mutation in this gene and has been reported in the homozygous and compound heterozygous states in association with Peters plus syndrome; this variant has also been reported as c.1020+1G>A (Lesnik Oberstein, 2006; Wang, 2020). This nucleotide position is highly conserved in available vertebrate species. Functional analysis demonstrated that 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, 2006). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.3

Eigen_PC

Pathogenic

1.2

FATHMM_MKL

Pathogenic

0.99

GERP RS

6.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over