VCV000001264.70 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(26)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 1264 Accession: VCV000001264.70

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q12.3 13: 31269278 (GRCh38) [ NCBI UCSC ] 13: 31843415 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 20, 2024	Jan 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_194318.4:c.660+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NC_000013.11:g.31269278G>A
NC_000013.10:g.31843415G>A
NG_011732.2:g.74304G>A

Protein change

Other names

B3GALTL, IVS8, G-A, +1
IVS8, G-A, +1

Canonical SPDI

NC_000013.11:31269277:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00069

The Genome Aggregation Database (gnomAD), exomes 0.00070

The Genome Aggregation Database (gnomAD) 0.00083

Trans-Omics for Precision Medicine (TOPMed) 0.00083

Links

ClinGen: CA224368 Genetic Testing Registry (GTR): GTR000558164 OMIM: 610308.0001 dbSNP: rs80338851 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
B3GLCT		-	-	GRCh38 GRCh37	277	337

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Peters plus syndrome	Pathogenic (16)	criteria provided, multiple submitters, no conflicts	Dec 22, 2023	RCV000001326.39
not provided	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Jan 1, 2024	RCV000082789.41
B3GLCT-related disorder	Pathogenic (1)	no assertion criteria provided	Aug 4, 2024	RCV003398411.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 14, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000280698.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016
Pathogenic (Apr 12, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peters plus syndrome Affected status: yes Allele origin: unknown	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Study: Clinvar_gadteam_Clinical_exome_analysis_3 Accession: SCV000803795.1 First in ClinVar: Aug 24, 2018 Last updated: Aug 24, 2018
Pathogenic (Dec 10, 2014)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000232806.5 First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=B3GLCT Number of individuals with the variant: 5 Sex: mixed
Pathogenic (Nov 10, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peters-plus syndrome Affected status: unknown Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV001448829.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1 Clinical Features: Microcephaly (present) , Short stature (present) , Gray matter heterotopias (present) , Abnormality of the cerebral white matter (present) , Clubfoot (present) , Hyporeflexia of … (more) Microcephaly (present) , Short stature (present) , Gray matter heterotopias (present) , Abnormality of the cerebral white matter (present) , Clubfoot (present) , Hyporeflexia of lower limbs (present) , Appendicular hypotonia (present) , Micrognathia (present) , Short toe (present) , Abnormality of the acetabulum (present) , Hip dislocation (present) , Infantile spasms (present) , Failure to thrive (present) , Cortical visual impairment (present) , Optic atrophy (present) , Short columella (present) , Long eyelashes (present) , Polymicrogyria (present) , Hemiplegia (present) , Global developmental delay (present) (less) Sex: male
Pathogenic (Oct 12, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peters plus syndrome Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001369876.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2,PP3.
Pathogenic (Apr 18, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Peters plus syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002547796.1 First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022	Publications: PubMed (3) PubMed: 18199743‚ 16909395‚ 32204707 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peters plus syndrome Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579682.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PM3_STR, PM2_SUP, PP1	Number of individuals with the variant: 1 Sex: female
Pathogenic (Dec 13, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peters plus syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002556402.2 First in ClinVar: Aug 04, 2022 Last updated: Dec 17, 2022	Publications: PubMed (1) PubMed: 16909395 Comment: 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 … (more) 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). (less)
Pathogenic (Jan 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peters plus syndrome Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807659.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 strong, PM3 strong Number of individuals with the variant: 1 Clinical Features: Retrognathia (present) , Brachydactyly (present) , Tip-toe gait (present) , Short long bone (present) , Decreased body weight (present) , Epicanthus (present) , Low-set ears … (more) Retrognathia (present) , Brachydactyly (present) , Tip-toe gait (present) , Short long bone (present) , Decreased body weight (present) , Epicanthus (present) , Low-set ears (present) , Telecanthus (present) , Upslanted palpebral fissure (present) , Happy demeanor (present) , Neurodevelopmental delay (present) , Skeletal dysplasia (present) , Smooth philtrum (present) , Delayed speech and language development (present) , Premature birth (present) , Frontal bossing (present) , Short stature (present) , Limb undergrowth (present) , Delayed ossification of carpal bones (present) (less) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002010931.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Peters plus syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000383588.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (7) PubMed: 20301637‚ 23889335‚ 19796186‚ 18798333‚ 23161355‚ 18199743‚ 16909395 Comment: 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 … (more) 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. (less)
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peters plus syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002521159.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Comment: 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. … (more) 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. (less) Clinical Features: Cleft palate (present) , Epicanthus (present) , Proptosis (present) , High palate (present)
Pathogenic (Sep 28, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Peters plus syndrome Affected status: unknown Allele origin: unknown	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill Study: CSER_NCGENES_2 Accession: SCV002587024.1 First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022 Comment: The B3GLCT c.660+1G>A variant is predicted to alter a canonical splice donor site and was previously reported as a pathogenic variant in multiple individuals with … (more) The B3GLCT c.660+1G>A variant is predicted to alter a canonical splice donor site and was previously reported as a pathogenic variant in multiple individuals with autosomal recessive Peters plus syndrome (PMIDs 16909395, 18798333, 31795264). B3GLCT c.660+1G>A was reported as the most common variant in individuals with Peters plus syndrome (PMID 20301637). Analysis of RNA from affected individuals suggested this variant resulted in exon 8 skipping and introduction of a frameshift and premature termination codon in exon 9 (PMID 16909395). This variant is also referred to as c.1020+1G>A in the literature and is observed in gnomAD v2.1.1 with a total allele frequency of 0.08% (214 alleles/281,510 alleles, 0 homozygotes). (less)	Number of individuals with the variant: 1 Clinical Features: Cryptorchidism (present) , Macrocephaly (present) , Abnormality of the outer ear (present) , Abnormal earlobe morphology (present) , Abnormal pinna morphology (present) , Thickened helices … (more) Cryptorchidism (present) , Macrocephaly (present) , Abnormality of the outer ear (present) , Abnormal earlobe morphology (present) , Abnormal pinna morphology (present) , Thickened helices (present) , Broad nasal tip (present) , Atypical behavior (present) , Depression (present) , Abnormality of the vertebral column (present) , Global developmental delay (present) , Obesity (present) , Clubfoot (present) , Delayed gross motor development (present) , Fibular aplasia (present) , Disproportionate short stature (present) , Short stature (present) , Increased body weight (present) , Aplasia/hypoplasia of the femur (present) , Short lower limbs (present) , Disproportionate short-limb short stature (present) , Neonatal short-limb short stature (present) , Large earlobe (present) , Lower limb undergrowth (present) , Abnormal helix morphology (present) , Mild global developmental delay (present) , Unilateral cryptorchidism (present) , Delayed ability to stand (present) , Delayed ability to sit (present) , Delayed ability to walk (present) , Hypertelorism (absent) , Preauricular skin tag (absent) , Conductive hearing impairment (absent) , Sensorineural hearing loss disorder (absent) , Strabismus (absent) , Visual impairment (absent) , Microphthalmia (absent) , Hypotelorism (absent) , Nystagmus (absent) , Congenital diaphragmatic hernia (absent) , Diabetes mellitus (absent) , Hyperpigmentation of the skin (absent) , Hypopigmentation of the skin (absent) , Cholestasis (absent) , Congenital omphalocele (absent) , Gastroschisis (absent) , Ventricular septal defect (absent) , Atrial septal defect (absent) , Tetralogy of Fallot (absent) , Complete atrioventricular canal (absent) , Coarctation of aorta (absent) , Exocrine pancreatic insufficiency (absent) , Toe syndactyly (absent) , Camptodactyly of toe (absent) , Esophageal atresia (absent) , Abnormality of the lung (absent) , Aganglionic megacolon (absent) , Tracheoesophageal fistula (absent) , Elevated circulating hepatic transaminase concentration (absent) , Preauricular pit (absent) , Capillary hemangioma (absent) , Finger syndactyly (absent) , Vascular skin abnormality (absent) , Cardiac arrhythmia (absent) , Preaxial polydactyly (absent) , Postaxial polydactyly (absent) , Camptodactyly of finger (absent) (less)
Pathogenic (Jan 06, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329095.10 First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Jan 25, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peters plus syndrome Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV003932257.1 First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023	Comment: PVS1, PM3_strong
Pathogenic (Jan 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peters plus syndrome Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004041470.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023
Pathogenic (Dec 22, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Peters plus syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000759969.9 First in ClinVar: Feb 15, 2018 Last updated: Feb 20, 2024	Publications: PubMed (10) PubMed: 28492532‚ 16199547‚ 18798333‚ 23889335‚ 16909395‚ 18199743‚ 19796186‚ 23161355‚ 23213277‚ 26684045 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001500571.23 First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024	Comment: B3GLCT: PVS1, PM2 Number of individuals with the variant: 3
Pathogenic (Nov 01, 2009)	no assertion criteria provided Method: literature only	PETERS-PLUS SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000021476.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 10, 2021	Publications: PubMed (4) PubMed: 16909395‚ 18199743‚ 18798333‚ 19796186 Comment on evidence: In 2 sibs with Peters-plus syndrome (PTRPLS; 261540) who had a microdeletion encompassing the B3GALTL gene on their maternal allele, Lesnik Oberstein et al. (2006) … (more) In 2 sibs with Peters-plus syndrome (PTRPLS; 261540) who had a microdeletion encompassing the B3GALTL gene on their maternal allele, Lesnik Oberstein et al. (2006) identified a 660+1G-A transition in the donor splice site of exon 8 of the B3GALTL gene on the paternal allele. Targeted sequencing analysis in an additional 18 Peters-plus patients from 15 families revealed homozygosity for the splice site mutation in 16 patients; in the remaining 2 patients (Dutch sibs), the mutation was found in compound heterozygosity with another splice site mutation (610308.0002). Fourteen patients were Dutch whites, and the other patients were Turkish, British, Arab, or Indian. Using an immunopurification-mass spectroscopy method, Hess et al. (2008) found that Peters-plus patients carrying the 660+1G-A mutation in B3GALTL showed only the fucosyl-O- modification in all 4 O-fucosylation sites of the reporter protein properdin (PFC; 300383). In contrast, properdin from heterozygous relatives and a healthy volunteer showed the glucosyl-beta-1,3-fucose-O- modification. Reis et al. (2008) identified homozygosity for the common 660+1G-A mutation in the B3GALTL gene in 2 patients, 1 Caucasian and 1 Hispanic, with Peter-plus syndrome. In 2 other Caucasian patients with this disorder, they identified compound heterozygosity for this mutation and either IVS6+1G-A (610308.0003) or 230insT (610308.0004). In a Sri Lankan patient with Peters-plus syndrome, Dassie-Ajdid et al. (2009) identified compound heterozygosity for the recurrent 660+1G-A mutation and a missense mutation (610308.0005) in the B3GALTL gene. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798532.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001739941.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927667.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001973416.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Aug 04, 2024)	no assertion criteria provided Method: clinical testing	B3GLCT-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004104109.2 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
Pathogenic (Mar 01, 2022)	no assertion criteria provided Method: clinical testing	Peters plus syndrome Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV002583408.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
not provided (-)	no classification provided Method: literature only	Peters plus syndrome Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000041737.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (3) PubMed: 16909395‚ 18199743‚ 20301637 BookShelf: NBK1464 BookShelf: NBK1464
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Comment:

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.

Comment:

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).

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Peters plus syndrome and Chorioretinal findings associated with B3GLCT gene mutation - a case report.	Wang YE	BMC ophthalmology	2020	PMID: 32204707
Peters Plus Syndrome.	Adam MP	-	2017	PMID: 20301637
Unique Presentation of Corneal Opacity in Peters Plus Syndrome: An Unusual Form of Peters Anomaly Showing Tissue Repair in Serial Analysis.	de Nie KF	Cornea	2016	PMID: 26684045
Novel B3GALTL mutations in classic Peters plus syndrome and lack of mutations in a large cohort of patients with similar phenotypes.	Weh E	Clinical genetics	2014	PMID: 23889335
Hydrocephalus, agenesis of the corpus callosum, and cleft lip/palate represent frequent associations in fetuses with Peters' plus syndrome and B3GALTL mutations. Fetal PPS phenotypes, expanded by Dandy Walker cyst and encephalocele.	Schoner K	Prenatal diagnosis	2013	PMID: 23161355
Absence of NR2E1 mutations in patients with aniridia.	Corso-Díaz X	Molecular vision	2012	PMID: 23213277
Novel B3GALTL mutation in Peters-plus Syndrome.	Dassie-Ajdid J	Clinical genetics	2009	PMID: 19796186
Mutation analysis of B3GALTL in Peters Plus syndrome.	Reis LM	American journal of medical genetics. Part A	2008	PMID: 18798333
Peters Plus syndrome is a new congenital disorder of glycosylation and involves defective Omicron-glycosylation of thrombospondin type 1 repeats.	Hess D	The Journal of biological chemistry	2008	PMID: 18199743
Peters Plus syndrome is caused by mutations in B3GALTL, a putative glycosyltransferase.	Lesnik Oberstein SA	American journal of human genetics	2006	PMID: 16909395
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=B3GLCT	-	-	-	-
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Text-mined citations for rs80338851 ...

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Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80338851 ...