NM_000335.5(SCN5A):c.3748G>A (p.Val1250Met) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Mar 1, 2021
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:: RCV000154838.17

Allele description [Variation Report for NM_000335.5(SCN5A):c.3748G>A (p.Val1250Met)]

NM_000335.5(SCN5A):c.3748G>A (p.Val1250Met)

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.3748G>A (p.Val1250Met)

Other names:

p.V1251M:GTG>ATG

HGVS:

NC_000003.12:g.38566498C>T
NG_008934.1:g.88175G>A
NM_000335.5:c.3748G>AMANE SELECT
NM_001099404.2:c.3751G>A
NM_001099405.2:c.3751G>A
NM_001160160.2:c.3748G>A
NM_001160161.2:c.3589G>A
NM_001354701.2:c.3748G>A
NM_198056.3:c.3751G>A
NP_000326.2:p.Val1250Met
NP_001092874.1:p.Val1251Met
NP_001092875.1:p.Val1251Met
NP_001153632.1:p.Val1250Met
NP_001153633.1:p.Val1197Met
NP_001341630.1:p.Val1250Met
NP_932173.1:p.Val1251Met
NP_932173.1:p.Val1251Met
LRG_289t1:c.3751G>A
LRG_289:g.88175G>A
LRG_289p1:p.Val1251Met
NC_000003.11:g.38607989C>T
NM_198056.2:c.3751G>A
Q14524:p.Val1251Met

Protein change:

V1197M

Links:

UniProtKB: Q14524#VAR_074418; dbSNP: rs199473600

NCBI 1000 Genomes Browser:

rs199473600

Molecular consequence:

NM_000335.5:c.3748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.3751G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.3751G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.3748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.3589G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.3748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.3751G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

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dad30h11.x1 Wellcome CRC pCS107 tropicalis St10-12 Xenopus tropicalis cDNA clone...
dad30h11.x1 Wellcome CRC pCS107 tropicalis St10-12 Xenopus tropicalis cDNA clone IMAGE:4441220 3', mRNA sequence
gi|13483303|gnl|dbEST|8223859|gb|BG 6.1|

Nucleotide
JGI_CABK10737.rev NIH_XGC_tropSpl1 Xenopus tropicalis cDNA clone IMAGE:7885752 3...
JGI_CABK10737.rev NIH_XGC_tropSpl1 Xenopus tropicalis cDNA clone IMAGE:7885752 3', mRNA sequence
gi|73844552|gnl|dbEST|31094980|gb|D 72.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000204520	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (May 16, 2015)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19841300, 24033266
SCV001519589	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Mar 1, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19841300, 32533946, 31751991 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000204520

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(May 16, 2015)

germline

clinical testing

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

SCV001519589

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Mar 1, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	2	1	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

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants.

Kapa S, Tester DJ, Salisbury BA, Harris-Kerr C, Pungliya MS, Alders M, Wilde AA, Ackerman MJ.

Circulation. 2009 Nov 3;120(18):1752-60. doi: 10.1161/CIRCULATIONAHA.109.863076. Epub 2009 Oct 19.

PubMed [citation]

PMID:: 19841300
PMCID:: PMC3025752

See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000204520.5

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

Description

Variant classified as Uncertain Significance - Favor Benign. The p.Val1251Met va riant in SCN5A has not been reported in any other families with DCM. However, it has been identified in a cohort of apparently unaffected African American indiv iduals (1/736 chromosomes; Kapa 2009), as well as in 0.2% (20/10346) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs199473600). Computational prediction tools and conservation analy sis do not provide strong support for or against an impact to the protein. In su mmary, while the clinical significance of the p.Val1251Met variant is uncertain, its frequency suggests that it is more likely to be benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001519589.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: SCN5A c.3751G>A (p.Val1251Met) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251448 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. c.3751G>A has been reported in the literature (example Kapa_2009. These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia/Brugada/Long QT syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in a high throughput patch clamp assay that resulted in re-classification of this variant as benign in accordance with the ACMG classification criteria (example, Glazer_2020). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3; VUS, n=3). Based on the evidence outlined above, the variant was classified as benign.

#	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: Oct 20, 2024

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