VCV000543808.6 - ClinVar

NM_000334.4(SCN4A):c.1328T>C (p.Leu443Pro)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Uncertain significance

2 out of 2 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000334.4(SCN4A):c.1328T>C (p.Leu443Pro)

Variation ID: 543808 Accession: VCV000543808.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q23.3 17: 63964592 (GRCh38) [ NCBI UCSC ] 17: 62041952 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 28, 2018	Feb 15, 2026	Nov 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000334.4:c.1328T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000325.4:p.Leu443Pro	missense
NC_000017.11:g.63964592A>G
NC_000017.10:g.62041952A>G
NG_011699.1:g.13327T>C

Protein change

L443P

Other names

NM_000334.4(SCN4A):c.1328T>C
p.Leu443Pro

Canonical SPDI

NC_000017.11:63964591:A:G

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA400635030 dbSNP: rs1555604153 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SCN4A		-	-	GRCh38 GRCh37	887	2460

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hyperkalemic periodic paralysis	Uncertain significance (1)	criteria provided, single submitter	Jun 20, 2022	RCV000654661.8
Neuromuscular disease	Uncertain significance (1)	criteria provided, single submitter	Nov 27, 2024	RCV004797616.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain Significance (Nov 27, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neuromuscular disease (Autosomal dominant inheritance)	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Study: GREGoR Consortium Accession: SCV005419125.1 First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024	Comment: show The heterozygous p.Leu443Pro variant in SCN4A was identified by our study in 1 individual with neuromuscular disease. While this gene is still lacking sufficient evidence to establish a dominant mode of inheritance, we believe this is a possible novel mode of inheritance for neuromuscular disease. Given the limited information about the mode of inheritance, the significance of the p.Leu443Pro variant is uncertain. If you have any additional information about functional evidence or other individuals with this phenotype that also have heterozygous variants in SCN4A we encourage you to reach out to us. (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Uncertain significance (Jun 20, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hyperkalemic periodic paralysis	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000776558.5 First in ClinVar: May 28, 2018 Last updated: Feb 15, 2026	Comment: show This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 443 of the SCN4A protein (p.Leu443Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 543808). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

The heterozygous p.Leu443Pro variant in SCN4A was identified by our study in 1 individual with neuromuscular disease. While this gene is still lacking sufficient evidence to establish a dominant mode of inheritance, we believe this is a possible novel mode of inheritance for neuromuscular disease. Given the limited information about the mode of inheritance, the significance of the p.Leu443Pro variant is uncertain. If you have any additional information about functional evidence or other individuals with this phenotype that also have heterozygous variants in SCN4A we encourage you to reach out to us.

Comment:

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 443 of the SCN4A protein (p.Leu443Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 543808). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs1555604153 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 15, 2026