NM_000335.5(SCN5A):c.3206C>T (p.Thr1069Met) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 31, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000766797.14

Allele description [Variation Report for NM_000335.5(SCN5A):c.3206C>T (p.Thr1069Met)]

NM_000335.5(SCN5A):c.3206C>T (p.Thr1069Met)

Genes:

LOC110121269:VISTA enhancer hs2177 [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.3206C>T (p.Thr1069Met)

Other names:

p.T1069M:ACG>ATG

HGVS:

NC_000003.12:g.38580953G>A
NG_008934.1:g.73720C>T
NG_053884.1:g.2692G>A
NM_000335.5:c.3206C>TMANE SELECT
NM_001099404.2:c.3206C>T
NM_001099405.2:c.3206C>T
NM_001160160.2:c.3206C>T
NM_001160161.2:c.3206C>T
NM_001354701.2:c.3206C>T
NM_198056.3:c.3206C>T
NP_000326.2:p.Thr1069Met
NP_001092874.1:p.Thr1069Met
NP_001092875.1:p.Thr1069Met
NP_001153632.1:p.Thr1069Met
NP_001153633.1:p.Thr1069Met
NP_001341630.1:p.Thr1069Met
NP_932173.1:p.Thr1069Met
NP_932173.1:p.Thr1069Met
LRG_289t1:c.3206C>T
LRG_289:g.73720C>T
LRG_289p1:p.Thr1069Met
NC_000003.11:g.38622444G>A
NM_198056.2:c.3206C>T
Q14524:p.Thr1069Met

Protein change:

T1069M

Links:

UniProtKB: Q14524#VAR_068334; dbSNP: rs199473187

NCBI 1000 Genomes Browser:

rs199473187

Molecular consequence:

NM_000335.5:c.3206C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.3206C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.3206C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.3206C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.3206C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.3206C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.3206C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000235435	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jul 24, 2019)	germline	clinical testing	Citation Link,
SCV000545063	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000235435

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jul 24, 2019)

germline

clinical testing

Citation Link,

SCV000545063

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Jan 31, 2024)

germline

clinical testing

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

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

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 GeneDx, SCV000235435.12

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

Description

Reported in individuals with LQTS or referred for LQTS genetic testing and in one infant with sudden unexplained death who also harbored additional variants in four other cardiac genes (Tester et al., 2005; Kapa et al., 2009; Kapplinger et al., 2009; Goldenberg et al., 2011; Kapplinger et al., 2015; Methner et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 67782; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19716085, 27435932, 31737537, 15840476, 16731473, 19841300, 21185501, 25904541, 28150151, 22581653, 28988457)

#	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 Invitae, SCV000545063.7

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

#	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: Jun 2, 2024

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