NM_001368067.1(LDB3):c.439G>A (p.Ala147Thr) AND Myofibrillar myopathy 4

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000004992.18

Allele description [Variation Report for NM_001368067.1(LDB3):c.439G>A (p.Ala147Thr)]

NM_001368067.1(LDB3):c.439G>A (p.Ala147Thr)

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_001368067.1(LDB3):c.439G>A (p.Ala147Thr)

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_001171610.1:c.784G>A
NM_001368067.1:c.439G>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 4
Synonyms:: Myofibrillar myopathy, ZASP-related; Zaspopathy (type)
Identifiers:: MONDO: MONDO:0012277; MedGen: C4721886; OMIM: 609452

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000025168	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 2005)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000545674	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15668942, 23263837, 24668811, 28492532
SCV002498642	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 10, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15668942, 18765652, 21676617, 23263837, 24668811, 28349680, 32721234, 25741868
SCV002768075	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18055494, 25741868

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	clinical testing
not provided	germline	not provided	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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000025168.4

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

Description

In 7 unrelated patients with myofibrillar myopathy (MFM4; 609452), Selcen and Engel (2005) identified a heterozygous c.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.

#	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 Invitae, SCV000545674.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 147 of the LDB3 protein (p.Ala147Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant myofibrillar myopathy (PMID: 15668942, 23263837). ClinVar contains an entry for this variant (Variation ID: 4727). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects LDB3 function (PMID: 24668811). 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

From Molecular Genetics, Royal Melbourne Hospital, SCV002498642.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change is predicted to replace alanine with threonine at codon 147 of the LDB3 protein (p.(Ala147Thr), also known as NM_007078.2:c.690-4733G>A). The alanine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the striated muscle ZASP-like motif in exon 6 of the skeletal muscle isoform (PMID: 28349680). There is a small physicochemical difference between alanine and threonine. The variant is absent in a large population cohort (gnomAD v2.1 and v3.1). It has been identified in multiple individuals with myofibrillar myopathy, including variable cardiac and neuropathic involvement, and segregates with disease in at least one large family (PMID: 15668942, 18765652, 21676617, 23263837, 32721234). The variant demonstrates isoform-specific disruption of skeletal muscle actin filaments in functional assays (PMID: 24668811). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/4 algorithms predict benign). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4_Moderate, PP1_Moderate, PS3_Supporting, PM2_Supporting.

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768075.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is the proposed mechanism of disease in this gene and is associated with myofibrillar myopathy 4 (MIM#609452). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple unrelated individuals with myofibrillar myopathy (ClinVar, PMID: 18055494). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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 12, 2024

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