NM_007078.3(LDB3):c.690-4733G>A AND Myofibrillar myopathy, ZASP-related

Clinical significance:Pathogenic (Last evaluated: Oct 25, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000004992.8

Allele description [Variation Report for NM_007078.3(LDB3):c.690-4733G>A]

NM_007078.3(LDB3):c.690-4733G>A

Genes:
LDB3:LIM domain binding 3 [Gene - OMIM - HGNC]
LOC110121486:VISTA enhancer hs2143 [Gene]
Variant type:
single nucleotide variant
Cytogenetic location:
10q23.2
Genomic location:
Preferred name:
NM_007078.3(LDB3):c.690-4733G>A
HGVS:
  • NC_000010.11:g.86687163G>A
  • NG_008876.1:g.23600G>A
  • NG_054099.1:g.3192G>A
  • NM_001080114.2:c.439G>A
  • NM_001080115.2:c.690-4733G>A
  • NM_001080116.1:c.439G>A
  • NM_001171610.2:c.784G>A
  • NM_001171611.2:c.784G>A
  • NM_001368063.1:c.690-4733G>A
  • NM_001368064.1:c.690-4733G>A
  • NM_001368065.1:c.690-4733G>A
  • NM_001368066.1:c.439G>A
  • NM_001368067.1:c.439G>A
  • NM_001368068.1:c.439G>A
  • NM_007078.3:c.690-4733G>AMANE SELECT
  • NP_001073583.1:p.Ala147Thr
  • NP_001073585.1:p.Ala147Thr
  • NP_001165081.1:p.Ala262Thr
  • NP_001165082.1:p.Ala262Thr
  • NP_001354995.1:p.Ala147Thr
  • NP_001354996.1:p.Ala147Thr
  • NP_001354997.1:p.Ala147Thr
  • LRG_385t1:c.690-4733G>A
  • LRG_385t2:c.439G>A
  • LRG_385:g.23600G>A
  • LRG_385p2:p.Ala147Thr
  • NC_000010.10:g.88446920G>A
  • NM_007078.2:c.690-4733G>A
Protein change:
A147T; ALA147THR
Links:
OMIM: 605906.0001; dbSNP: rs121908333
NCBI 1000 Genomes Browser:
rs121908333
Molecular consequence:
  • NM_001080115.2:c.690-4733G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001368063.1:c.690-4733G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001368064.1:c.690-4733G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001368065.1:c.690-4733G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007078.3:c.690-4733G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001080114.2:c.439G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001080116.1:c.439G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001171610.2:c.784G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001171611.2:c.784G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368066.1:c.439G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368067.1:c.439G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368068.1:c.439G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Myofibrillar myopathy, ZASP-related (MFM4)
Synonyms:
MYOPATHY, MYOFIBRILLAR, 4; Zaspopathy (type)
Identifiers:
MONDO: MONDO:0012277; MedGen: C4721886; OMIM: 609452

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000025168OMIMno assertion criteria providedPathogenic
(Feb 1, 2005)
germlineliterature only

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

SCV000545674Invitaecriteria provided, single submitter
Pathogenic
(Oct 25, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Mutations in ZASP define a novel form of muscular dystrophy in humans.

Selcen D, Engel AG.

Ann Neurol. 2005 Feb;57(2):269-76.

PubMed [citation]
PMID:
15668942

[Myofibrillary myopathy due to the ZASP mutation Ala147Thr : two cases with exclusively distal leg involvement].

Kraya T, Kress W, Stoevesant D, Deschauer M, Zierz S.

Nervenarzt. 2013 Feb;84(2):209-13. doi: 10.1007/s00115-012-3689-0. German.

PubMed [citation]
PMID:
23263837
See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000025168.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In 7 unrelated patients with myofibrillar myopathy (MFM4; 609452), Selcen and Engel (2005) identified a heterozygous 464G-A transition in exon 6 of the LDB3 gene, resulting in an ala147-to-thr (A147T) substitution in a conserved region immediately before the ZM motif needed for interaction with alpha-actinin (see, e.g., ACTN1, 102575). Five patients had a family history of the disorder; the A147T mutation was identified in affected family members of 1 proband. All patients had progressive proximal and/or distal weakness, 3 patients had cardiac involvement, and 2 had evidence of peripheral neuropathy. The mutation was not identified in 220 control alleles.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000545674.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces alanine with threonine at codon 147 of the LDB3 protein (p.Ala147Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (rs121908333, ExAC no frequency). This variant has been reported in many unrelated individuals affected with myofibrillar myopathy (PMID: 15668942, 23263837). ClinVar contains an entry for this variant (Variation ID: 4727). Experimental studies have shown that this missense change disrupts actin stress fibers in transfected mouse muscle cells (PMID: 24668811). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2021

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