NM_000335.5(SCN5A):c.2848C>T (p.Pro950Ser) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 5, 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:: RCV000183013.4

Allele description [Variation Report for NM_000335.5(SCN5A):c.2848C>T (p.Pro950Ser)]

NM_000335.5(SCN5A):c.2848C>T (p.Pro950Ser)

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.2848C>T (p.Pro950Ser)

Other names:

p.P950S:CCT>TCT

HGVS:

NC_000003.12:g.38581311G>A
NG_008934.1:g.73362C>T
NG_053884.1:g.3050G>A
NM_000335.5:c.2848C>TMANE SELECT
NM_001099404.2:c.2848C>T
NM_001099405.2:c.2848C>T
NM_001160160.2:c.2848C>T
NM_001160161.2:c.2848C>T
NM_001354701.2:c.2848C>T
NM_198056.3:c.2848C>T
NP_000326.2:p.Pro950Ser
NP_001092874.1:p.Pro950Ser
NP_001092875.1:p.Pro950Ser
NP_001153632.1:p.Pro950Ser
NP_001153633.1:p.Pro950Ser
NP_001153633.1:p.Pro950Ser
NP_001341630.1:p.Pro950Ser
NP_932173.1:p.Pro950Ser
NP_932173.1:p.Pro950Ser
LRG_289t1:c.2848C>T
LRG_289:g.73362C>T
LRG_289p1:p.Pro950Ser
NC_000003.11:g.38622802G>A
NM_001160161.1:c.2848C>T
NM_198056.2:c.2848C>T

Protein change:

P950S

Links:

dbSNP: rs794728870

NCBI 1000 Genomes Browser:

rs794728870

Molecular consequence:

NM_000335.5:c.2848C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.2848C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.2848C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.2848C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.2848C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.2848C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.2848C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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uncharacterized protein LOC101218440 [Cucumis sativus]
uncharacterized protein LOC101218440 [Cucumis sativus]
gi|778685423|ref|XP_004136794.2|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000235420	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Aug 25, 2012)	germline	clinical testing	Citation Link,
SCV002149260	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 5, 2023)	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

SCV000235420

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Aug 25, 2012)

germline

clinical testing

Citation Link,

SCV002149260

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 5, 2023)

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV000235420.9

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

Description

p.Pro950Ser (CCT>TCT):c.2848 C>T in exon 17 of the SCN5A gene (NM_198056.2) The Pro950Ser variant in the SCN5A gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Pro950Ser results in a non-conservative amino acid substitution of non-polar Proline with a neutral, polar Serine at a position that is conserved across species. The NHLBI ESP Exome Variant Server reports Pro950Ser was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. However, in silico analysis predicts Pro950Ser likely has a benign effect on the protein structure/function. In addition, no mutations have been reported in surrounding residues to date, indicating this region of the protein may tolerate change. In summary, the clinical significance of the Pro950Ser variant in the SCN5A gene is currently unknown. The variant is found in LQT panel(s).

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002149260.3

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

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: 201481). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 950 of the SCN5A protein (p.Pro950Ser).

#	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: Nov 3, 2024

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