NM_000701.8(ATP1A1):c.2152G>A (p.Gly718Ser) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 14, 2024
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:: RCV003323097.2

Allele description [Variation Report for NM_000701.8(ATP1A1):c.2152G>A (p.Gly718Ser)]

NM_000701.8(ATP1A1):c.2152G>A (p.Gly718Ser)

Genes:

ATP1A1-AS1:ATP1A1 antisense RNA 1 [Gene - OMIM - HGNC]
ATP1A1:ATPase Na+/K+ transporting subunit alpha 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p13.1

Genomic location:

Preferred name:

NM_000701.8(ATP1A1):c.2152G>A (p.Gly718Ser)

HGVS:

NC_000001.11:g.116398648G>A
NG_047036.1:g.31464G>A
NM_000701.8:c.2152G>AMANE SELECT
NM_001160233.2:c.2152G>A
NM_001160234.2:c.2059G>A
NP_000692.2:p.Gly718Ser
NP_001153705.1:p.Gly718Ser
NP_001153706.1:p.Gly687Ser
NC_000001.10:g.116941270G>A

Protein change:

G687S

Molecular consequence:

NM_000701.8:c.2152G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160233.2:c.2152G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160234.2:c.2059G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004028133	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Feb 16, 2023)	germline	clinical testing	Citation Link,
SCV004261007	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 14, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 35110381, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004028133

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Feb 16, 2023)

germline

clinical testing

Citation Link,

SCV004261007

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 14, 2024)

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	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

De Novo ATP1A1 Variants in an Early-Onset Complex Neurodevelopmental Syndrome.

Dohrn MF, Rebelo AP, Srivastava S, Cappuccio G, Smigiel R, Malhotra A, Basel D, van de Laar I, Neuteboom RF, Aarts-Tesselaar C, Mahida S, Brunetti-Pierri N, Taft RJ, Züchner S.

Neurology. 2022 Mar 15;98(11):440-445. doi: 10.1212/WNL.0000000000013276. Epub 2022 Feb 2.

PubMed [citation]

PMID:: 35110381
PMCID:: PMC8935442

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

Details of each submission

From GeneDx, SCV004028133.1

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35110381, 36738336)

#	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, SCV004261007.1

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 718 of the ATP1A1 protein (p.Gly718Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of ATP1A1-related conditions (PMID: 35110381). ClinVar contains an entry for this variant (Variation ID: 2576792). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP1A1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP1A1 function (PMID: 35110381). 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.

#	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: Feb 20, 2024

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