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NM_000334.4(SCN4A):c.4527G>C (p.Lys1509Asn) AND SCN4A-related myopathy, autosomal recessive

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 4, 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:
RCV003994709.1

Allele description [Variation Report for NM_000334.4(SCN4A):c.4527G>C (p.Lys1509Asn)]

NM_000334.4(SCN4A):c.4527G>C (p.Lys1509Asn)

Genes:
GH-LCR:growth hormone locus control region [Gene]
SCN4A:sodium voltage-gated channel alpha subunit 4 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q23.3
Genomic location:
Preferred name:
NM_000334.4(SCN4A):c.4527G>C (p.Lys1509Asn)
HGVS:
  • NC_000017.11:g.63941755C>G
  • NG_011699.1:g.36164G>C
  • NG_042788.1:g.24663C>G
  • NM_000334.4:c.4527G>CMANE SELECT
  • NP_000325.4:p.Lys1509Asn
  • NC_000017.10:g.62019115C>G
Protein change:
K1509N
Molecular consequence:
  • NM_000334.4:c.4527G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
SCN4A-related myopathy, autosomal recessive
Identifiers:
MONDO: MONDO:0100121; MedGen: CN294783

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004812704Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Aug 4, 2022) 		germlineclinical testing

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

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Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV004812704.1

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

Description

This sequence change in SCN4A is predicted to replace lysine with asparagine at codon 1509, p.(Lys1509Asn). The lysine residue is moderately conserved (100 vertebrates, UCSC), and is located in the extracellular loop between the S5DIV and S6DIV domains. There is a moderate physicochemical difference between lysine and asparagine. This variant is present in a single individual in gnomAD v3.1 in the European (non-Finnish) population (1/68,040 alleles). To our knowledge, this variant has not been reported in the literature in any individuals with SCN4A-related disease. Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting.

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

Last Updated: Apr 20, 2024