NM_007078.3(LDB3):c.76C>T (p.Pro26Ser) AND Myofibrillar myopathy 4

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 25, 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:: RCV002540245.4

Allele description [Variation Report for NM_007078.3(LDB3):c.76C>T (p.Pro26Ser)]

NM_007078.3(LDB3):c.76C>T (p.Pro26Ser)

Gene:

LDB3:LIM domain binding 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q23.2

Genomic location:

Preferred name:

NM_007078.3(LDB3):c.76C>T (p.Pro26Ser)

Other names:

NM_007078.3(LDB3):c.76C>T; p.Pro26Ser

HGVS:

NC_000010.11:g.86668767C>T
NG_008876.1:g.5204C>T
NM_001080114.2:c.76C>T
NM_001080115.2:c.76C>T
NM_001080116.1:c.76C>T
NM_001171610.2:c.76C>T
NM_001171611.2:c.76C>T
NM_001368063.1:c.76C>T
NM_001368064.1:c.76C>T
NM_001368065.1:c.76C>T
NM_001368066.1:c.76C>T
NM_001368067.1:c.76C>T
NM_001368068.1:c.76C>T
NM_007078.3:c.76C>TMANE SELECT
NP_001073583.1:p.Pro26Ser
NP_001073584.1:p.Pro26Ser
NP_001073585.1:p.Pro26Ser
NP_001165081.1:p.Pro26Ser
NP_001165082.1:p.Pro26Ser
NP_001354992.1:p.Pro26Ser
NP_001354993.1:p.Pro26Ser
NP_001354994.1:p.Pro26Ser
NP_001354995.1:p.Pro26Ser
NP_001354996.1:p.Pro26Ser
NP_001354997.1:p.Pro26Ser
NP_009009.1:p.Pro26Ser
LRG_385t2:c.76C>T
LRG_385:g.5204C>T
LRG_385p2:p.Pro26Ser
NC_000010.10:g.88428524C>T
NC_000010.11:g.86668767C>T

Protein change:

P26S

Links:

dbSNP: rs778865072

NCBI 1000 Genomes Browser:

rs778865072

Molecular consequence:

NM_001080114.2:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001080115.2:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001080116.1:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001171610.2:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001171611.2:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001368063.1:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001368064.1:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001368065.1:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001368066.1:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001368067.1:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001368068.1:c.76C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_007078.3:c.76C>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
SCV003314142	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 19, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33308939, 28492532
SCV003761232	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 25, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003314142

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 19, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV003761232

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 25, 2023)

germline

curation

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

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, curation

Citations

PubMed

Protein aggregates and autophagy involvement in a family with a mutation in Z-band alternatively spliced PDZ-motif protein.

Cassandrini D, Merlini L, Pilla F, Cenni V, Santi S, Faldini C, Santorelli FM, Sabatelli P.

Neuromuscul Disord. 2021 Jan;31(1):44-51. doi: 10.1016/j.nmd.2020.11.008. Epub 2020 Nov 20.

PubMed [citation]

PMID:: 33308939

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003314142.2

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

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1305257). This missense change has been observed in individual(s) with myofibrillar myopathy (PMID: 33308939). This variant is present in population databases (rs778865072, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 26 of the LDB3 protein (p.Pro26Ser).

#	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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003761232.1

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

Description

The heterozygous p.Pro26Ser variant in LDB3 was identified by our study in one individual with congenital myopathy. The p.Pro26Ser variant in LDB3 has been previously reported in two siblings with myopathy (PMID: 33308939) but has been identified in 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs778865072). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID:1305257) and has been interpreted as a variant of uncertain significance by GeneDx. The p.Pro26Ser variant is located in a region of LDB3 that is essential to myofibrillar integrity, suggesting that this variant is in a functional domain and slightly supports pathogenicity ((PMID: 10427098, 15062084). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Pro26Ser variant is uncertain. ACMG/AMP Criteria applied: PM1_Supporting (Richards 2015).

#	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

ClinVar

Relating variation to medicine