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NM_001164508.2(NEB):c.7431+1919_7536+374del AND Arthrogryposis multiplex congenita 6

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 1, 2009
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV001449896.9

Allele description [Variation Report for NM_001164508.2(NEB):c.7431+1919_7536+374del]

NM_001164508.2(NEB):c.7431+1919_7536+374del

Gene:
NEB:nebulin [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
2q23.3
Genomic location:
Preferred name:
NM_001164508.2(NEB):c.7431+1919_7536+374del
Other names:
R2478_D2512del
HGVS:
  • NC_000002.12:g.151645758_151648259del
  • NG_009382.2:g.91229_93730del
  • NG_009382.2:g.91231_93732del
  • NM_001164507.2:c.7431+1919_7536+374del
  • NM_001164508.2:c.7431+1919_7536+374delMANE SELECT
  • NM_001271208.2:c.7431+1919_7536+374del
  • NM_004543.4:c.7432-2025_7536+372del
  • NM_004543.5:c.7431+1919_7536+374del
  • LRG_202:g.91231_93732del
  • NC_000002.11:g.152502272_152504773del
  • NG_009382.2:g.91229_93730del
  • NM_004543.3:c.7432-2025_7536+372del
  • NM_004543.3:c.7622-2025_7727+372del2502
  • NP_004534?.2:p.Arg2478_Asp2512del
  • c.7432-2025_7536+372del2502
  • NM_004543.3:c.7622-2025_7727+372del2502
Links:
Genetic Testing Registry (GTR): GTR000575392; LOVD 3: NEB_000007; dbVar: nssv3761583; dbVar: nsv1067832; OMIM: 161650.0007
Molecular consequence:
  • NM_001164507.2:c.7431+1919_7536+374del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001164508.2:c.7431+1919_7536+374del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001271208.2:c.7431+1919_7536+374del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_004543.5:c.7431+1919_7536+374del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001164507.2:c.7431+1919_7536+374del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001164508.2:c.7431+1919_7536+374del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001271208.2:c.7431+1919_7536+374del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_004543.5:c.7431+1919_7536+374del - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Arthrogryposis multiplex congenita 6
Identifiers:
MONDO: MONDO:0030281; MedGen: C5543431; OMIM: 619334

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001653292OMIM
no assertion criteria provided
Pathogenic
(Jul 1, 2009)
germlineliterature only

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

The exon 55 deletion in the nebulin gene--one single founder mutation with world-wide occurrence.

Lehtokari VL, Greenleaf RS, DeChene ET, Kellinsalmi M, Pelin K, Laing NG, Beggs AH, Wallgren-Pettersson C.

Neuromuscul Disord. 2009 Mar;19(3):179-81. doi: 10.1016/j.nmd.2008.12.001. Epub 2009 Feb 15.

PubMed [citation]
PMID:
19232495
PMCID:
PMC2713598

Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene.

Anderson SL, Ekstein J, Donnelly MC, Keefe EM, Toto NR, LeVoci LA, Rubin BY.

Hum Genet. 2004 Aug;115(3):185-90. Epub 2004 Jun 23.

PubMed [citation]
PMID:
15221447
See all PubMed Citations (5)

Details of each submission

From OMIM, SCV001653292.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (5)

Description

Nemaline Myopathy 2

In 5 affected individuals from 5 Ashkenazi Jewish families with autosomal recessive typical nemaline myopathy (NEM2; 256030), Anderson et al. (2004) identified a homozygosity for a 2,502-bp deletion completely encompassing exon 55 and parts of introns 54 and 55 of the NEB gene, predicted to result in a transcript encoding 35 fewer amino acids. Screening for this mutation in a random sample of 4,090 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 108.

Lehtokari et al. (2009) identified the 2,502-bp deletion in 14 of 355 probands with nemaline myopathy from around the world; 2 of the probands had been reported by Anderson et al. (2004). Seven probands were homozygous for the deletion, and 7 carried the mutation in heterozygosity. Two of the families were not of known Ashkenazi Jewish descent, but carried the common haplotype identified in Ashkenazi Jews. The findings were consistent with a founder effect.

Ottenheijm et al. (2009) studied the muscular phenotype of nemaline myopathy patients with NEB exon 55 deletion (NM-NEB). SDS-PAGE and Western blot analysis revealed greatly reduced nebulin levels in skeletal muscle of NM-NEB patients, with the most prominent reduction at nebulin's N-terminal end. Muscle mechanical studies indicated an approximately 60% reduced force generating capacity of NM-NEB muscle and a leftward shift of the force-sarcomere length relation in NM-NEB muscle fibers. This indicates that the mechanism for the force reduction is likely to include shorter and nonuniform thin filament lengths in NM-NEB muscle compared with control muscle. The average thin filament length was reduced from approximately 1.3-micrometer in control muscle to approximately 0.75-micrometer in NM-NEB muscle. Ottenheijm et al. (2009) hypothesized that dysregulated thin filament length may contribute to muscle weakness in nemaline myopathy patients with nebulin mutations.

Arthrogryposis Multiplex Congenita 6

Yonath et al. (2012) reported 4 unrelated pregnancies with abnormal prenatal ultrasound findings in fetuses with arthrogryposis multiplex congenita-6 (AMC6; 619334). In each family, 1 or both of the parents was of Ashkenazi Jewish descent, and the common exon 55 deletion in the NEB gene was found in the heterozygous state in the patients and in unaffected parents. A second pathogenic NEB mutation was found in 3 of the patients; a second mutation could not be identified in 1 of the patients. Prenatal ultrasound showed polyhydramnios, decreased fetal movements, clubfoot, and clenched hands. All patients showed severe hypotonia after birth, and all died within the first months of life.

Feingold-Zadok et al. (2017) identified this mutation in 2 fetal sibs with AMC6 from an Ashkenazi Jewish family (family 1), in compound heterozygosity with a splice site mutation.

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

Last Updated: Jun 17, 2024