VCV000201500.2 - ClinVar

NM_000335.5(SCN5A):c.3820G>T (p.Asp1274Tyr)

Germline

Classification

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Pathogenic
Pathogenic (1)

This classification is based on the single submission received

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_000335.5(SCN5A):c.3820G>T (p.Asp1274Tyr)

Variation ID: 201500 Accession: VCV000201500.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 38566426 (GRCh38) [ NCBI UCSC ] 3: 38607917 (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 29, 2016	May 29, 2016	Jan 15, 2014

HGVS

Nucleotide	Protein	Molecular consequence
NM_000335.5:c.3820G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000326.2:p.Asp1274Tyr	missense
NM_001099404.2:c.3823G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001092874.1:p.Asp1275Tyr	missense
NM_001099405.2:c.3823G>T	NP_001092875.1:p.Asp1275Tyr	missense
NM_001160160.2:c.3820G>T	NP_001153632.1:p.Asp1274Tyr	missense
NM_001160161.2:c.3661G>T	NP_001153633.1:p.Asp1221Tyr	missense
NM_001354701.2:c.3820G>T	NP_001341630.1:p.Asp1274Tyr	missense
NM_198056.3:c.3823G>T	NP_932173.1:p.Asp1275Tyr	missense
NC_000003.12:g.38566426C>A
NC_000003.11:g.38607917C>A
NG_008934.1:g.88247G>T
LRG_289:g.88247G>T
LRG_289t1:c.3823G>T	LRG_289p1:p.Asp1275Tyr

... more HGVS ... less HGVS

Protein change

D1274Y, D1275Y, D1221Y

Other names

p.D1275Y:GAC>TAC

Canonical SPDI

NC_000003.12:38566425:C:A

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: CA017536 dbSNP: rs137854618 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	4571	5098

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.
not provided	Pathogenic (1)	criteria provided, single submitter	Jan 15, 2014	RCV000183046.2

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.
Pathogenic (Jan 15, 2014) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000235455.10 First in ClinVar: Jul 05, 2015 Last updated: May 29, 2016	Comment: show The D1275Y mutation in the SCN5A gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Mutations affecting this same residue (D1275N) and nearby residues (N1269S, W1271C, V1281F) have been reported in association with Brugada syndrome and arrhythmia, supporting the functional importance of this residue and this region of the protein. D1275Y is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The D1275Y position is highly conserved across species and in silico analysis predicts D1275Y is damaging to the protein structure/function. Furthermore, D1275Y was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is found in BRUGADA panel(s). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

The D1275Y mutation in the SCN5A gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Mutations affecting this same residue (D1275N) and nearby residues (N1269S, W1271C, V1281F) have been reported in association with Brugada syndrome and arrhythmia, supporting the functional importance of this residue and this region of the protein. D1275Y is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The D1275Y position is highly conserved across species and in silico analysis predicts D1275Y is damaging to the protein structure/function. Furthermore, D1275Y was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is found in BRUGADA panel(s).

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 rs137854618 ...

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 05, 2022