NM_001368067.1(LDB3):c.494C>T (p.Ala165Val) AND Myofibrillar myopathy 4

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Nov 13, 2023
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:: RCV000004993.17

Allele description [Variation Report for NM_001368067.1(LDB3):c.494C>T (p.Ala165Val)]

NM_001368067.1(LDB3):c.494C>T (p.Ala165Val)

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.494C>T (p.Ala165Val)

HGVS:

NC_000010.11:g.86687218C>T
NG_008876.1:g.23655C>T
NG_054099.1:g.3247C>T
NM_001080114.2:c.494C>T
NM_001080115.2:c.690-4678C>T
NM_001080116.1:c.494C>T
NM_001171610.2:c.839C>T
NM_001171611.2:c.839C>T
NM_001368063.1:c.690-4678C>T
NM_001368064.1:c.690-4678C>T
NM_001368065.1:c.690-4678C>T
NM_001368066.1:c.494C>T
NM_001368067.1:c.494C>T
NM_001368068.1:c.494C>T
NM_007078.3:c.690-4678C>TMANE SELECT
NP_001073583.1:p.Ala165Val
NP_001073585.1:p.Ala165Val
NP_001165081.1:p.Ala280Val
NP_001165082.1:p.Ala280Val
NP_001354995.1:p.Ala165Val
NP_001354996.1:p.Ala165Val
NP_001354997.1:p.Ala165Val
LRG_385t1:c.690-4678C>T
LRG_385t2:c.494C>T
LRG_385:g.23655C>T
LRG_385p2:p.Ala165Val
NC_000010.10:g.88446975C>T
NM_001080114.1:c.494C>T
NM_007078.2:c.690-4678C>T
c.494C>T

Protein change:

A165V; ALA165VAL

Links:

OMIM: 605906.0002; dbSNP: rs121908334

NCBI 1000 Genomes Browser:

rs121908334

Molecular consequence:

NM_001080115.2:c.690-4678C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001368063.1:c.690-4678C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001368064.1:c.690-4678C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001368065.1:c.690-4678C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_007078.3:c.690-4678C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001080114.2:c.494C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001080116.1:c.494C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001171610.2:c.839C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001171611.2:c.839C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001368066.1:c.494C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001368067.1:c.494C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001368068.1:c.494C>T - 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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000025169	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 2007)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 15668942, 4855680, 17337483
SCV000965091	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 13, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15668942, 25208129, 24647531, 24668811, 28492532
SCV002038571	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Pathogenic (Apr 7, 2021)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15668942, 17337483, 18765652, 24668811, 25208129, 33742095 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000025169

OMIM

no assertion criteria provided

Pathogenic
(Jun 1, 2007)

germline

literature only

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

SCV000965091

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 13, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002038571

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)

Pathogenic
(Apr 7, 2021)

unknown

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Late onset hereditary distal myopathy.

Markesbery WR, Griggs RC, Leach RP, Lapham LW.

Neurology. 1974 Feb;24(2):127-34. No abstract available.

PubMed [citation]

PMID:: 4855680

ZASP interacts with the mechanosensing protein Ankrd2 and p53 in the signalling network of striated muscle.

Martinelli VC, Kyle WB, Kojic S, Vitulo N, Li Z, Belgrano A, Maiuri P, Banks L, Vatta M, Valle G, Faulkner G.

PLoS One. 2014;9(3):e92259. doi: 10.1371/journal.pone.0092259. Retraction in: PLoS One. 2024 Jan 31;19(1):e0298249. doi: 10.1371/journal.pone.0298249.

PubMed [citation]

PMID:: 24647531
PMCID:: PMC3960238

See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000025169.5

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

Description

In 3 unrelated patients with myofibrillar myopathy (MFM4; 609452), Selcen and Engel (2005) identified a heterozygous c.519C-T transition in exon 6 of the LDB3 gene, resulting in an ala165-to-val (A165V) substitution within the ZM motif needed for interaction with alpha-actinin (see, e.g., ACTN1, 102575). Two patients had a family history of the disorder. All had progressive weakness that was more severe distally, 1 had cardiac involvement, and 2 had evidence of peripheral neuropathy. The mutation was not identified in 220 control alleles.

In affected members of a large multigenerational family with adult-onset distal myopathy originally reported by Markesbery et al. (1974), Griggs et al. (2007) identified a heterozygous A165V mutation in the ZASP gene. Haplotype analysis of this family and in 5 other families of European ancestry with this mutation showed a founder effect. Western blot analysis of patient skeletal muscle showed normal amount of ZASP protein isoforms similar to controls. Functional studies of the variant were not performed.

#	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, SCV000965091.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 165 of the LDB3 protein (p.Ala165Val). This variant is present in population databases (rs121908334, gnomAD 0.0009%). This missense change has been observed in individuals with myofibrillar myopathy (PMID: 15668942, 25208129). ClinVar contains an entry for this variant (Variation ID: 4728). 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: 24647531, 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 Illumina Laboratory Services, Illumina, SCV002038571.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The LDB3 c.494C>T (p.Ala165Val) variant, also referred to as c.690-4678C>T, is a missense variant that has been reported in at least seven unrelated individuals with myofibrillar myopathy presenting with progressive muscle weakness, mainly distally, and myopathic motor unit potentials noted through electromyography. Muscle atrophy, tripping episodes, walking difficulty, peripheral neuropathy, decreased reflexes in the legs, tingling and numbness in the feet, and ankle movement problems were also noted in some individuals (Selcen and Engler 2005; Griggs et al. 2007; Fischer et al. 2008; Semmler et al. 2014). Only one individual had cardiac problems presenting as prolonged QT (Selec and Engler 2005). The p.Ala165Val variant segregated with disease in a large pedigree where six affected individuals carried the variant. Three additional family members who carried the variant were asymptomatic at the time of the study, but they ranged in age from 39-49 years (Griggs et al. 2007). In functional studies using a mouse model or cells derived from mice, the phenotype observed in humans was recapitulated when the p.Ala165Val variant was present in a heterozygous state. This included presence of muscle weakness, characteristic muscle fiber structural abnormalities, protein aggregation patterns, and Z-disc disruption generally observed in myofibrillar myopathy (Lin et al. 2014; Pathak et al. 2014). The p.Ala165Val variant is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database, but this is based on one allele in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence, the p.Ala165Val variant is classified as pathogenic for myofibrillar myopathy.

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

Last Updated: Jun 23, 2024

ClinVar

Relating variation to medicine