NM_000335.5(SCN5A):c.3732G>A (p.Met1244Ile) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jun 7, 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:: RCV001729846.4

Allele description [Variation Report for NM_000335.5(SCN5A):c.3732G>A (p.Met1244Ile)]

NM_000335.5(SCN5A):c.3732G>A (p.Met1244Ile)

Gene:

SCN5A:sodium voltage-gated channel alpha subunit 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000335.5(SCN5A):c.3732G>A (p.Met1244Ile)

HGVS:

NC_000003.12:g.38566514C>T
NG_008934.1:g.88159G>A
NM_000335.5:c.3732G>AMANE SELECT
NM_001099404.2:c.3735G>A
NM_001099405.2:c.3735G>A
NM_001160160.2:c.3732G>A
NM_001160161.2:c.3573G>A
NM_001354701.2:c.3732G>A
NM_198056.3:c.3735G>A
NP_000326.2:p.Met1244Ile
NP_001092874.1:p.Met1245Ile
NP_001092875.1:p.Met1245Ile
NP_001153632.1:p.Met1244Ile
NP_001153633.1:p.Met1191Ile
NP_001341630.1:p.Met1244Ile
NP_932173.1:p.Met1245Ile
LRG_289:g.88159G>A
NC_000003.11:g.38608005C>T

Protein change:

M1191I

Links:

dbSNP: rs753677814

NCBI 1000 Genomes Browser:

rs753677814

Molecular consequence:

NM_000335.5:c.3732G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.3735G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.3735G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.3732G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.3573G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.3732G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.3735G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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MAG: Chromatiales bacterium isolate bin74 chromosome
MAG: Chromatiales bacterium isolate bin74 chromosome
gi|2108311572|gb|CP070671.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001514844	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 7, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27554632, 28492532
SCV001978434	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing
SCV001979443	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001514844

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 7, 2020)

germline

clinical testing

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

SCV001978434

Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided

Likely benign

germline

clinical testing

SCV001979443

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided

Likely benign

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Analysis of SCN5A Gene Variants in East Slovak Patients with Cardiomyopathy.

Priganc M, Zigová M, Boroňová I, Bernasovská J, Dojčáková D, Szabadosová V, Mydlárová Blaščáková M, Tóthová I, Kmec J, Bernasovský I.

J Clin Lab Anal. 2017 Mar;31(2). doi: 10.1002/jcla.22037. Epub 2016 Aug 24.

PubMed [citation]

PMID:: 27554632
PMCID:: PMC6816823

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, SCV001514844.3

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

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with dilated cardiomyopathy or hypertrophic cardiomyopathy (PMID: 27554632). This variant is present in population databases (rs753677814, ExAC 0.001%). This sequence change replaces methionine with isoleucine at codon 1245 of the SCN5A protein (p.Met1245Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine.

#	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

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001978434.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001979443.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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