NM_152490.5(B3GALNT2):c.802G>A (p.Val268Met) AND Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 11

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: May 9, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000034848.18

Allele description [Variation Report for NM_152490.5(B3GALNT2):c.802G>A (p.Val268Met)]

NM_152490.5(B3GALNT2):c.802G>A (p.Val268Met)

Gene:

B3GALNT2:beta-1,3-N-acetylgalactosaminyltransferase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q42.3

Genomic location:

Preferred name:

NM_152490.5(B3GALNT2):c.802G>A (p.Val268Met)

Other names:

B3GALNT2, VAL268MET

HGVS:

NC_000001.11:g.235465675C>T
NG_033219.2:g.43807G>A
NM_001277155.3:c.925G>A
NM_152490.5:c.802G>AMANE SELECT
NP_001264084.1:p.Val309Met
NP_689703.1:p.Val268Met
NC_000001.10:g.235628992C>T
NM_152490.3:c.802G>A
NM_152490.4:c.802G>A
Q8NCR0:p.Val268Met
p.(Val268Met)

Protein change:

V268M; VAL268MET

Links:

UniProtKB: Q8NCR0#VAR_069640; OMIM: 610194.0005; dbSNP: rs367543074

NCBI 1000 Genomes Browser:

rs367543074

Molecular consequence:

NM_001277155.3:c.925G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_152490.5:c.802G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 11 (MDDGA11)
Synonyms:: WALKER-WARBURG SYNDROME OR MUSCLE-EYE-BRAIN DISEASE, B3GALNT2-RELATED; Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A11; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 11
Identifiers:: MONDO: MONDO:0014071; MedGen: C3554638; Orphanet: 588; Orphanet: 899; OMIM: 615181

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000058418	OMIM	no assertion criteria provided	Pathogenic (Mar 7, 2013)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000244035	ClinVar Staff, National Center for Biotechnology Information (NCBI)	no assertion criteria provided	Likely pathogenic (Jun 27, 2013)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000772921	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 9, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23453667, 29273094, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000058418

OMIM

no assertion criteria provided

Pathogenic
(Mar 7, 2013)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000244035

ClinVar Staff, National Center for Biotechnology Information (NCBI)

no assertion criteria provided

Likely pathogenic
(Jun 27, 2013)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000772921

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 9, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of α-dystroglycan.

Stevens E, Carss KJ, Cirak S, Foley AR, Torelli S, Willer T, Tambunan DE, Yau S, Brodd L, Sewry CA, Feng L, Haliloglu G, Orhan D, Dobyns WB, Enns GM, Manning M, Krause A, Salih MA, Walsh CA, Hurles M, Campbell KP, Manzini MC; et al.

Am J Hum Genet. 2013 Mar 7;92(3):354-65. doi: 10.1016/j.ajhg.2013.01.016. Epub 2013 Feb 28.

PubMed [citation]

PMID:: 23453667
PMCID:: PMC3591840

B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype-phenotype associations in the muscular dystrophy-dystroglycanopathies.

Maroofian R, Riemersma M, Jae LT, Zhianabed N, Willemsen MH, Wissink-Lindhout WM, Willemsen MA, de Brouwer APM, Mehrjardi MYV, Ashrafi MR, Kusters B, Kleefstra T, Jamshidi Y, Nasseri M, Pfundt R, Brummelkamp TR, Abbaszadegan MR, Lefeber DJ, van Bokhoven H.

Genome Med. 2017 Dec 22;9(1):118. doi: 10.1186/s13073-017-0505-2.

PubMed [citation]

PMID:: 29273094
PMCID:: PMC5740572

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000058418.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a girl, born of consanguineous Saudi Arabian parents, with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A11 (MDDGA11; 615181), Stevens et al. (2013) identified a homozygous 802G-A transition in exon 7 of the B3GALNT2 gene, resulting in a val268-to-met (V268M) substitution at a conserved residue. Each unaffected parent was heterozygous for the mutation, which was found by exome sequencing. She presented at age 15 months with delayed psychomotor development and brain abnormalities, including frontotemporal leukoencephalopathy and cerebellar dysplasia. The mutant protein showed diffuse intracellular localization compared to wildtype, which localized to the endoplasmic reticulum.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000244035.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000772921.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 268 of the B3GALNT2 protein (p.Val268Met). This variant is present in population databases (rs367543074, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital muscular dystrophy (PMID: 23453667). ClinVar contains an entry for this variant (Variation ID: 41938). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on B3GALNT2 function (PMID: 23453667, 29273094). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 26, 2024

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