NM_001164508.2(NEB):c.12018+1G>A AND Nemaline myopathy 2

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Dec 3, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000593350.6

Allele description [Variation Report for NM_001164508.2(NEB):c.12018+1G>A]

NM_001164508.2(NEB):c.12018+1G>A

Gene:
NEB:nebulin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q23.3
Genomic location:
Preferred name:
NM_001164508.2(NEB):c.12018+1G>A
HGVS:
  • NC_000002.12:g.151610515C>T
  • NG_009382.2:g.128973G>A
  • NM_001164507.2:c.12018+1G>A
  • NM_001164508.2:c.12018+1G>AMANE SELECT
  • NM_001271208.2:c.12018+1G>A
  • NM_004543.5:c.11289+1G>A
  • LRG_202t1:c.12018+1G>A
  • LRG_202:g.128973G>A
  • NC_000002.11:g.152467029C>T
  • NM_001271208.1:c.12018+1G>A
Links:
dbSNP: rs762278237
NCBI 1000 Genomes Browser:
rs762278237
Molecular consequence:
  • NM_001164507.2:c.12018+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001164508.2:c.12018+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001271208.2:c.12018+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_004543.5:c.11289+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Nemaline myopathy 2 (NEM2)
Synonyms:
Nemaline myopathy caused by mutation in the nebulin gene; Nemaline myopathy 2, autosomal recessive
Identifiers:
MONDO: MONDO:0009725; MedGen: C1850569; OMIM: 256030

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000832679Invitaecriteria provided, single submitter
Pathogenic
(Nov 15, 2017)
germlineclinical testing

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

SCV001132440Counsylno assertion criteria providedPathogenic
(Dec 28, 2016)
unknownclinical testing

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

SCV001164420Broad Institute Rare Disease Group, Broad Institutecriteria provided, single submitter
Likely pathogenic
(Dec 3, 2018)
germlineresearch

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

SCV001760060Genomics England Pilot Project,Genomics Englandno assertion criteria provided
Pathogenicgermlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing, research
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Mutation update: the spectra of nebulin variants and associated myopathies.

Lehtokari VL, Kiiski K, Sandaradura SA, Laporte J, Repo P, Frey JA, Donner K, Marttila M, Saunders C, Barth PG, den Dunnen JT, Beggs AH, Clarke NF, North KN, Laing NG, Romero NB, Winder TL, Pelin K, Wallgren-Pettersson C.

Hum Mutat. 2014 Dec;35(12):1418-26. doi: 10.1002/humu.22693.

PubMed [citation]
PMID:
25205138
PMCID:
PMC4295925
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000832679.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change affects a donor splice site in intron 80 of the NEB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs762278237, ExAC 0.003%). This variant has been reported in two families affected with autosomal recessive nemaline myopathy (PMID: 25205138). ClinVar contains an entry for this variant (Variation ID: 265494). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). For these reasons, this variant has been classified as Pathogenic.

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

From Counsyl, SCV001132440.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Broad Institute Rare Disease Group, Broad Institute, SCV001164420.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (2)

Description

The heterozygous c.12018+1G>A variant in NEB was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with nemaline myopathy. This variant has been reported in the compound heterozygous state, with a splice site variant and a frameshift variant, in two additional, unrelated individuals (PMID: 25205138). The presence of this variant in combination with a reported pathogenic variant and in several individual with nemaline myopathy increases the likelihood that the c.12018+1G>A variant is pathogenic. This variant has been identified in 0.002981% (1/33548) of Latino chromosomes and 0.001798% (2/111260) of European (non-Finnish) chromsomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762278237). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The c.12018+1G>A variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to remove a splicing site, causing abnormal splicing that does not result in a frameshift in the reading frame. Loss of function of the NEB gene is an established disease mechanism for autosomal recessive nemaline myopathy. In summary, although additional studies are required to fully establish its clinical significance, the c.12018+1G>A variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1_Moderate, PM3_Strong (Richards 2015).

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

From Genomics England Pilot Project,Genomics England, SCV001760060.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 30, 2021

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