NM_000335.5(SCN5A):c.3061C>T (p.Pro1021Ser) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: May 30, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000766796.11

Allele description [Variation Report for NM_000335.5(SCN5A):c.3061C>T (p.Pro1021Ser)]

NM_000335.5(SCN5A):c.3061C>T (p.Pro1021Ser)

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.3061C>T (p.Pro1021Ser)

Other names:

p.P1021S:CCC>TCC

HGVS:

NC_000003.12:g.38581098G>A
NG_008934.1:g.73575C>T
NG_053884.1:g.2837G>A
NM_000335.5:c.3061C>TMANE SELECT
NM_001099404.2:c.3061C>T
NM_001099405.2:c.3061C>T
NM_001160160.2:c.3061C>T
NM_001160161.2:c.3061C>T
NM_001354701.2:c.3061C>T
NM_198056.3:c.3061C>T
NP_000326.2:p.Pro1021Ser
NP_001092874.1:p.Pro1021Ser
NP_001092875.1:p.Pro1021Ser
NP_001153632.1:p.Pro1021Ser
NP_001153633.1:p.Pro1021Ser
NP_001341630.1:p.Pro1021Ser
NP_932173.1:p.Pro1021Ser
NP_932173.1:p.Pro1021Ser
LRG_289t1:c.3061C>T
LRG_289:g.73575C>T
LRG_289p1:p.Pro1021Ser
NC_000003.11:g.38622589G>A
NM_198056.2:c.3061C>T

Protein change:

P1021S

Links:

dbSNP: rs794728871

NCBI 1000 Genomes Browser:

rs794728871

Molecular consequence:

NM_000335.5:c.3061C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.3061C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.3061C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.3061C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.3061C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.3061C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.3061C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000235425	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Feb 8, 2017)	germline	clinical testing	Citation Link,
SCV001494310	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 30, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23174487, 28492532
SCV002501542	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 23, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23174487, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000235425

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Feb 8, 2017)

germline

clinical testing

Citation Link,

SCV001494310

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 30, 2023)

germline

clinical testing

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

SCV002501542

AiLife Diagnostics, AiLife Diagnostics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 23, 2021)

germline

clinical testing

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

Help

Summary from all submissions

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

Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations.

Mullally J, Goldenberg I, Moss AJ, Lopes CM, Ackerman MJ, Zareba W, McNitt S, Robinson JL, Benhorin J, Kaufman ES, Towbin JA, Barsheshet A.

Heart Rhythm. 2013 Mar;10(3):378-82. doi: 10.1016/j.hrthm.2012.11.006. Epub 2012 Nov 19.

PubMed [citation]

PMID:: 23174487
PMCID:: PMC3690288

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000235425.13

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

Description

The P1021S variant has been reported in one individual with LQTS (Mullally et al., 2013), though no clinical or segregation data was provided. The P1021S variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although P1021S has been seen in multiple individuals referred for LQTS testing at GeneDx, segregation data is not sufficient due to the lack of clinical information provided and/or insufficient participation by informative family members. The P1021S variant, located in the DII/DIII intracellular loop, results in a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. Consequently, in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.

#	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, SCV001494310.3

#	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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 201484). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 23174487). This variant is present in population databases (rs794728871, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1021 of the SCN5A protein (p.Pro1021Ser).

#	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 AiLife Diagnostics, AiLife Diagnostics, SCV002501542.1

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

#	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		1	not provided	not provided	not provided

Last Updated: Jun 2, 2024

ClinVar

Relating variation to medicine