1-116395247-C-G

Variant names:

• chr1-116395247-C-G
• rs1553192091
• NM_000701.8:c.1798C>G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_000701.8(ATP1A1):​c.1798C>G​(p.Pro600Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P600R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A1 NM_000701.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 7.90

Genes affected

ATP1A1 (HGNC:799): (ATPase Na+/K+ transporting subunit alpha 1) The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta). The catalytic subunit of Na+/K+ -ATPase is encoded by multiple genes. This gene encodes an alpha 1 subunit. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

ATP1A1-AS1 (HGNC:28262): (ATP1A1 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a helix (size 9) in uniprot entity AT1A1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000701.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-116395248-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1685248.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the ATP1A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 6.2154 (above the threshold of 3.09). Trascript score misZ: 8.228 (above the threshold of 3.09). GenCC associations: The gene is linked to hypomagnesemia, seizures, and intellectual disability 2, charcot-marie-tooth disease, axonal, type 2DD.
• PP5: Variant 1-116395247-C-G is Pathogenic according to our data. Variant chr1-116395247-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 545678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-116395247-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A1	NM_000701.8	c.1798C>G	p.Pro600Ala	missense_variant	Exon 13 of 23	ENST00000295598.10	NP_000692.2
ATP1A1	NM_001160233.2	c.1798C>G	p.Pro600Ala	missense_variant	Exon 13 of 23		NP_001153705.1
ATP1A1	NM_001160234.2	c.1705C>G	p.Pro569Ala	missense_variant	Exon 13 of 23		NP_001153706.1
ATP1A1-AS1	NR_027646.1	n.401-2221G>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A1	ENST00000295598.10	c.1798C>G	p.Pro600Ala	missense_variant	Exon 13 of 23	1	NM_000701.8	ENSP00000295598.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-tooth disease, axonal, type 2DD Pathogenic:3

Dec 06, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change is predicted to replace proline with alanine at codon 600 of the ATP1A1 protein, p.(Pro600Ala). The proline residue is evolutionarily conserved (100 vertebrates, Multiz alignments), and is located in a mutational hot spot in the helical linker region that couples ATP hydrolysis and phosphorylation domains (PMID: 29499166). There is a small physicochemical difference between proline and alanine. This variant is absent from the population database gnomAD v4.1. It has been identified in at least two probands with sensorimotor axonal neuropathy and segregates with disease over three generations in a large family (PMID: 29499166, Royal Melbourne Hospital). Induced pluripotent stem cell-derived motor neurons from an affected individual demonstrated defective differentiation and absence of ATP1A1 expression (PMID: 31707753). Additionally, in vitro functional assays demonstrated significantly fewer Na+-dependent currents for the variant (PMID: 29499166). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.652) and predicts no impact on splicing (SpliceAI) for the nucleotide change. Furthermore, a different missense change at this position (p.Pro600Thr) has been identified in a family with Charcot-Marie-Tooth disease (PMID: 29499166). Based on the classification scheme RMH Modified ACMG Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PM1, PS3_Supporting, PS4_Supporting, PM2_Supporting, PP4. -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth disease, axonal, type 2DD (MIM#618036) and hypomagnesemia, seizures, and mental retardation 2 (MIM#618314). Loss of function has been clearly established for missense variants however, there is currently no information in the literature on the mechanism of disease associated with ATP1A1 protein truncating variants (PMIDs: 29499166, 30388404; OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to alanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated helical linker region (PMID: 29499166). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Pro600Thr) variant has been reported in one American family with Charcot-Marie-Tooth type 2 disease where the variant was found to segregate in four affected individuals (PMID: 29499166). (SP) 0803 - This variant has limited previous evidence of pathogenicity. This variant has been reported in one Italian family with Charcot-Marie-Tooth type 2 disease (PMID: 29499166). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate in at least five affected individuals within the same family (PMID: 29499166). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Pluripotent stem cells (iPSCs) generated from patient fibroblasts demonstrated defective differentiation of neuronal precursors into mature motor neurons in vitro compared to control iPSCs (PMID: 31707753). Additionally, mutant ATP1A1 expressed in Xenopus oocytes demonstrated significantly reduced Na+-dependent currents and using ouabain survival assays in U2OS cells, Lassuthova et al. (2018) also showed that mutant constructs had significantly reduced cell viability significantly reduced cell viability (PMID: 29499166) . (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jun 28, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jul 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 600 of the ATP1A1 protein (p.Pro600Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 29499166). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 545678). 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 not expected to disrupt ATP1A1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ATP1A1 function (PMID: 29499166). This variant disrupts the p.Pro600 amino acid residue in ATP1A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29499166). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease type 2A2 Uncertain:1

Oct 07, 2017

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Uncertain	-0.015	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.1	D;D;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.034	D;D;D
Polyphen		0.94	P;.;.
Vest4		0.56
MutPred		0.62		Loss of methylation at K605 (P = 0.0502);Loss of methylation at K605 (P = 0.0502);.;
MVP		0.83
MPC		2.3
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.67
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553192091; hg19: chr1-116937869;