NM_021971.4(GMPPB):c.972dup (p.Val325fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 28, 2023
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:: RCV002971529.3

Allele description [Variation Report for NM_021971.4(GMPPB):c.972dup (p.Val325fs)]

NM_021971.4(GMPPB):c.972dup (p.Val325fs)

Gene:

GMPPB:GDP-mannose pyrophosphorylase B [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

3p21.31

Genomic location:

Preferred name:

NM_021971.4(GMPPB):c.972dup (p.Val325fs)

HGVS:

NC_000003.12:g.49721863dup
NG_011603.1:g.37307dup
NG_033731.2:g.7112dup
NM_013334.4:c.1053dup
NM_021971.4:c.972dupMANE SELECT
NP_037466.3:p.Val352fs
NP_068806.2:p.Val325fs
NC_000003.11:g.49759295_49759296insT
NC_000003.11:g.49759296dup

Protein change:

V325fs

Molecular consequence:

NM_013334.4:c.1053dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_021971.4:c.972dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14
Synonyms:: WALKER-WARBURG SYNDROME OR MUSCLE-EYE-BRAIN DISEASE, GMPPB-RELATED; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 14; Congenital Muscular Dystrophy-Dystroglycanopathy with Brain and Eye Anomalies Type A 14; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0014140; MedGen: C3809216; Orphanet: 588; OMIM: 615350

Name:: Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 (MDDGB14)
Synonyms:: MUSCULAR DYSTROPHY, CONGENITAL, GMPPB-RELATED; Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type B14; MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH IMPAIRED INTELLECTUAL DEVELOPMENT), TYPE B, 14
Identifiers:: MONDO: MONDO:0014141; MedGen: C3809221; OMIM: 615351

Name:: Autosomal recessive limb-girdle muscular dystrophy type 2T
Synonyms:: MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY, LIMB-GIRDLE, GMPPB-RELATED; MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2T; Muscular dystrophy-dystroglycanopathy (limb-girdle), type c, 14; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0014142; MedGen: C4518000; Orphanet: 363623; OMIM: 615352

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003282638	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 28, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28433477, 33756069, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003282638

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 28, 2023)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel mutations in the C-terminal region of GMPPB causing limb-girdle muscular dystrophy overlapping with congenital myasthenic syndrome.

Luo S, Cai S, Maxwell S, Yue D, Zhu W, Qiao K, Zhu Z, Zhou L, Xi J, Lu J, Beeson D, Zhao C.

Neuromuscul Disord. 2017 Jun;27(6):557-564. doi: 10.1016/j.nmd.2017.03.004. Epub 2017 Mar 10.

PubMed [citation]

PMID:: 28433477

Congenital myasthenic syndrome in China: genetic and myopathological characterization.

Zhao Y, Li Y, Bian Y, Yao S, Liu P, Yu M, Zhang W, Wang Z, Yuan Y.

Ann Clin Transl Neurol. 2021 Apr;8(4):898-907. doi: 10.1002/acn3.51346. Epub 2021 Mar 23.

PubMed [citation]

PMID:: 33756069
PMCID:: PMC8045908

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003282638.2

#	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 creates a premature translational stop signal (p.Val325Serfs*4) in the GMPPB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acid(s) of the GMPPB protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with GMPPB-related conditions. ClinVar contains an entry for this variant (Variation ID: 2070938). This variant disrupts a region of the GMPPB protein in which other variant(s) (p.Arg357His) have been determined to be pathogenic (PMID: 28433477, 33756069). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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: Sep 29, 2024

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