NM_152296.5(ATP1A3):c.2324C>T (p.Pro775Leu) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Sep 1, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000272828.29

Allele description [Variation Report for NM_152296.5(ATP1A3):c.2324C>T (p.Pro775Leu)]

NM_152296.5(ATP1A3):c.2324C>T (p.Pro775Leu)

Gene:

ATP1A3:ATPase Na+/K+ transporting subunit alpha 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.2

Genomic location:

Preferred name:

NM_152296.5(ATP1A3):c.2324C>T (p.Pro775Leu)

HGVS:

NC_000019.10:g.41970482G>A
NG_008015.1:g.28749C>T
NM_001256213.2:c.2357C>T
NM_001256214.2:c.2363C>T
NM_152296.5:c.2324C>TMANE SELECT
NP_001243142.1:p.Pro786Leu
NP_001243143.1:p.Pro788Leu
NP_689509.1:p.Pro775Leu
LRG_1186t1:c.2324C>T
LRG_1186:g.28749C>T
LRG_1186p1:p.Pro775Leu
NC_000019.9:g.42474634G>A
NM_001256213.2:c.2357C>T
NM_001256214.1:c.2363C>T
NM_152296.3:c.2324C>T
NM_152296.4:c.2324C>T

Protein change:

P775L

Links:

dbSNP: rs886041396

NCBI 1000 Genomes Browser:

rs886041396

Molecular consequence:

NM_001256213.2:c.2357C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001256214.2:c.2363C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_152296.5:c.2324C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000329981	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Nov 9, 2017)	germline	clinical testing	Citation Link,
SCV000609780	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 1, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001151935	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Jun 1, 2019)	germline	clinical testing	Citation Link,
SCV002064420	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 1, 2021)	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	4	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000329981.6

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

Description

The P775L pathogenic variant in the ATP1A3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The P775L variant has been observed as a de novo variant with confirmed parentage in multiple patients with neurodevelopmental disorders previously tested at GeneDx. The P775L variant is not observed in large population cohorts (Lek et al., 2016). The P775L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P775L as a pathogenic variant.

#	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 Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000609780.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	0.000092	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001151935.22

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	not provided

#	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		4	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002064420.1

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

Description

DNA sequence analysis of the ATP1A3 gene demonstrated a sequence change, c.2324C>T, in exon 17 that results in an amino acid change, p.Pro775Leu. This sequence change is absent in the gnomAD population database. The p.Pro775Leu change has been previously described as a de novo variant in individuals with ATP1A3-related disorders (PMID: 32684337, https://n.neurology.org/content/94/15_Supplement/1946). The p.Pro775Leu change affects a moderately conserved amino acid residue located in a domain of the ATP1A3 protein that is known to be functional. The p.Pro775Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL, CADD). The vast majority of pathogenic variants in the ATP1A3 gene are missense with many located around the p.Pro775 region. In addition, the ATP1A3 gene appears to be relatively intolerant to missense changes. Collectively this evidence suggests p.Pro775Leu is likely pathogenic, however functional studies have not been performed to prove this conclusively.

#	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

Last Updated: May 12, 2024

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