VCV000345117.18 - ClinVar

NM_000335.5(SCN5A):c.3460C>T (p.Pro1154Ser)

Germline

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.

(13)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000335.5(SCN5A):c.3460C>T (p.Pro1154Ser)

Variation ID: 345117 Accession: VCV000345117.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 38576709 (GRCh38) [ NCBI UCSC ] 3: 38618200 (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	Dec 6, 2016	May 1, 2024	Dec 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000335.5:c.3460C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000326.2:p.Pro1154Ser	missense
NM_001099404.2:c.3463C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001092874.1:p.Pro1155Ser	missense
NM_001099405.2:c.3463C>T	NP_001092875.1:p.Pro1155Ser	missense
NM_001160160.2:c.3460C>T	NP_001153632.1:p.Pro1154Ser	missense
NM_001160161.2:c.3301C>T	NP_001153633.1:p.Pro1101Ser	missense
NM_001354701.2:c.3460C>T	NP_001341630.1:p.Pro1154Ser	missense
NM_198056.3:c.3463C>T	NP_932173.1:p.Pro1155Ser	missense
NC_000003.12:g.38576709G>A
NC_000003.11:g.38618200G>A
NG_008934.1:g.77964C>T
LRG_289:g.77964C>T
LRG_289t1:c.3463C>T	LRG_289p1:p.Pro1155Ser

... more HGVS ... less HGVS

Protein change

P1154S, P1155S, P1101S

Other names

Canonical SPDI

NC_000003.12:38576708:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

Links

ClinGen: CA061870 dbSNP: rs781103369 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.
SCN5A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3783	4225

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.
Sick sinus syndrome 1	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000299399.6
Congenital long QT syndrome	Uncertain significance (1)	criteria provided, single submitter	Jun 14, 2016	RCV000287616.6
Ventricular fibrillation, paroxysmal familial, type 1	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000314661.6
Brugada syndrome 1	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV001094943.5
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jul 30, 2023	RCV001653665.5
Long QT syndrome 3	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000403001.6
Progressive familial heart block, type 1A	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000345003.6
Dilated cardiomyopathy 1E	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000403733.6
Cardiac arrhythmia	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV003591728.3
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Jul 28, 2023	RCV002338944.3
Atrial fibrillation, familial, 10 Brugada syndrome 1 Dilated cardiomyopathy 1E Long QT syndrome 3 Progressive familial heart block, type 1A SUDDEN INFANT DEATH SYNDROME Sick sinus syndrome 1 Ventricular fibrillation, paroxysmal familial, type 1	Uncertain significance (1)	criteria provided, single submitter	Aug 19, 2021	RCV002487513.1
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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.	More information 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 (Jun 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiac arrhythmia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV004361656.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Comment: This missense variant replaces proline with serine at codon 1155 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces proline with serine at codon 1155 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/238042 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain Significance (Dec 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiac arrhythmia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004814457.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Comment: This missense variant replaces proline with serine at codon 1155 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces proline with serine at codon 1155 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/238042 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 6
Uncertain significance (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Romano-Ward Syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000443985.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Ventricular fibrillation, paroxysmal familial, type 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000443988.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Long QT syndrome 3 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000443990.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Dilated cardiomyopathy 1E Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000443987.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Sick sinus syndrome 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000443991.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Brugada syndrome 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000443989.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Progressive familial heart block, type 1A Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000443986.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Aug 25, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001871374.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 345117; … (more) Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 345117; Landrum et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26582918) (less)
Uncertain significance (Jul 30, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001217966.4 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Comment: 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 … (more) 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 345117). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is present in population databases (rs781103369, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1155 of the SCN5A protein (p.Pro1155Ser). (less)
Uncertain significance (Aug 19, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Progressive familial heart block, type 1A SUDDEN INFANT DEATH SYNDROME Brugada syndrome 1 Dilated cardiomyopathy 1E Ventricular fibrillation, paroxysmal familial, type 1 Long QT syndrome 3 Sick sinus syndrome 1 Atrial fibrillation, familial, 10 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002785959.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Jul 28, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002618659.3 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.P1155S variant (also known as c.3463C>T), located in coding exon 18 of the SCN5A gene, results from a C to T substitution at nucleotide … (more) The p.P1155S variant (also known as c.3463C>T), located in coding exon 18 of the SCN5A gene, results from a C to T substitution at nucleotide position 3463. The proline at codon 1155 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Comment:

This missense variant replaces proline with serine at codon 1155 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/238042 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 345117; Landrum et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26582918)

Comment:

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 345117). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is present in population databases (rs781103369, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1155 of the SCN5A protein (p.Pro1155Ser).

Comment:

The p.P1155S variant (also known as c.3463C>T), located in coding exon 18 of the SCN5A gene, results from a C to T substitution at nucleotide position 3463. The proline at codon 1155 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

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 rs781103369 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000335.5(SCN5A):c.3460C>T (p.Pro1154Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs781103369 ...