NM_152393.4(KLHL40):c.631del (p.Ala211fs) AND Nemaline myopathy 8

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 29, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000815537.3

Allele description [Variation Report for NM_152393.4(KLHL40):c.631del (p.Ala211fs)]

NM_152393.4(KLHL40):c.631del (p.Ala211fs)

Gene:

KLHL40:kelch like family member 40 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

3p22.1

Genomic location:

Preferred name:

NM_152393.4(KLHL40):c.631del (p.Ala211fs)

HGVS:

NC_000003.12:g.42686249del
NG_033035.1:g.5731del
NM_152393.4:c.631delMANE SELECT
NP_689606.2:p.Ala211fs
NC_000003.11:g.42727740del
NC_000003.11:g.42727741del
NM_152393.3:c.631delG

Protein change:

A211fs

Links:

dbSNP: rs752734208

NCBI 1000 Genomes Browser:

rs752734208

Molecular consequence:

NM_152393.4:c.631del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000955996	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 29, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23746549, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000955996

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 29, 2020)

germline

clinical testing

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

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

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, SCV000955996.3

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

Description

This sequence change creates a premature translational stop signal (p.Ala211Leufs*47) in the KLHL40 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in KLHL40 are known to be pathogenic (PMID: 23746549). This variant has not been reported in the literature in individuals with KLHL40-related conditions. ClinVar contains an entry for this variant (Variation ID: 658674).

#	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: Feb 14, 2024

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