NM_152393.4(KLHL40):c.1152+2T>A AND Nemaline myopathy 8

Clinical significance:Likely pathogenic (Last evaluated: Dec 12, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000808744.1

Allele description [Variation Report for NM_152393.4(KLHL40):c.1152+2T>A]

NM_152393.4(KLHL40):c.1152+2T>A

Gene:
KLHL40:kelch like family member 40 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p22.1
Genomic location:
Preferred name:
NM_152393.4(KLHL40):c.1152+2T>A
HGVS:
  • NC_000003.12:g.42686772T>A
  • NG_033035.1:g.6254T>A
  • NM_152393.4:c.1152+2T>AMANE SELECT
  • NC_000003.11:g.42728264T>A
  • NM_152393.3:c.1152+2T>A
Links:
dbSNP: rs1575219191
NCBI 1000 Genomes Browser:
rs1575219191
Molecular consequence:
  • NM_152393.4:c.1152+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Nemaline myopathy 8 (NEM8)
Identifiers:
MONDO: MONDO:0014138; MedGen: C3809209; Orphanet: 171430; OMIM: 615348

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000948862Invitaecriteria provided, single submitter
Likely pathogenic
(Dec 12, 2018)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.

Ravenscroft G, Miyatake S, Lehtokari VL, Todd EJ, Vornanen P, Yau KS, Hayashi YK, Miyake N, Tsurusaki Y, Doi H, Saitsu H, Osaka H, Yamashita S, Ohya T, Sakamoto Y, Koshimizu E, Imamura S, Yamashita M, Ogata K, Shiina M, Bryson-Richardson RJ, Vaz R, et al.

Am J Hum Genet. 2013 Jul 11;93(1):6-18. doi: 10.1016/j.ajhg.2013.05.004. Epub 2013 Jun 6.

PubMed [citation]
PMID:
23746549
PMCID:
PMC3710748

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

Details of each submission

From Invitae, SCV000948862.1

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

Description

This sequence change affects a donor splice site in intron 1 of the KLHL40 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KLHL40-related conditions. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in KLHL40 are known to be pathogenic (PMID: 23746549). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Oct 7, 2021

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