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NM_152393.4(KLHL40):c.238G>C (p.Asp80His) AND Nemaline myopathy 8

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Sep 27, 2022
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:
RCV000792241.5

Allele description [Variation Report for NM_152393.4(KLHL40):c.238G>C (p.Asp80His)]

NM_152393.4(KLHL40):c.238G>C (p.Asp80His)

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.238G>C (p.Asp80His)
HGVS:
  • NC_000003.12:g.42685856G>C
  • NG_033035.1:g.5338G>C
  • NM_152393.2:c.238G>C
  • NM_152393.4:c.238G>CMANE SELECT
  • NP_689606.2:p.Asp80His
  • NC_000003.11:g.42727348G>C
  • NM_152393.3:c.238G>C
Protein change:
D80H
Links:
dbSNP: rs144461124
NCBI 1000 Genomes Browser:
rs144461124
Molecular consequence:
  • NM_152393.4:c.238G>C - missense variant - [Sequence Ontology: SO:0001583]

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000931522Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Sep 27, 2022) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000931522.4

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 80 of the KLHL40 protein (p.Asp80His). This variant is present in population databases (rs144461124, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with KLHL40-related conditions. ClinVar contains an entry for this variant (Variation ID: 639447). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KLHL40 protein function. 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.

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

Last Updated: Sep 29, 2024