NM_181703.4(GJA5):c.433del (p.Leu145fs) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 14, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000688023.4

Allele description [Variation Report for NM_181703.4(GJA5):c.433del (p.Leu145fs)]

NM_181703.4(GJA5):c.433del (p.Leu145fs)

Gene:

GJA5:gap junction protein alpha 5 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

1q21.2

Genomic location:

Preferred name:

NM_181703.4(GJA5):c.433del (p.Leu145fs)

HGVS:

NC_000001.11:g.147758808del
NG_009369.2:g.19569del
NM_005266.7:c.433del
NM_181703.4:c.433delMANE SELECT
NP_005257.2:p.Leu145fs
NP_859054.1:p.Leu145fs
NC_000001.10:g.147230914del
NC_000001.10:g.147230916del
NM_005266.5:c.433del
NM_005266.6:c.433delC

Protein change:

L145fs

Links:

dbSNP: rs781802553

NCBI 1000 Genomes Browser:

rs781802553

Molecular consequence:

NM_005266.7:c.433del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_181703.4:c.433del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Atrial standstill 1 (ATRST1)
Synonyms:: ATRIAL CARDIOMYOPATHY WITH HEART BLOCK; CARDIOMYOPATHY, FAMILIAL, WITH CONDUCTION DISTURBANCE; Atrial standstill, digenic (GJA5/SCN5A)
Identifiers:: MONDO: MONDO:0007171; MedGen: C4551959; Orphanet: 1344; OMIM: 108770

Name:: Atrial fibrillation, familial, 11 (ATFB11)
Identifiers:: MONDO: MONDO:0013544; MedGen: C3279693; OMIM: 614049

Recent activity

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PREDICTED: Homo sapiens regulating synaptic membrane exocytosis 2 (RIMS2), trans...
PREDICTED: Homo sapiens regulating synaptic membrane exocytosis 2 (RIMS2), transcript variant X23, mRNA
gi|2217373924|ref|XM_005251106.4|

Nucleotide
calmodulin C [Haliotis discus hannai]
calmodulin C [Haliotis discus hannai]
gi|1101417788|gb|APB96946.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000815619	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 14, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34495297, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000815619

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 14, 2023)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes.

Yoneda ZT, Anderson KC, Quintana JA, O'Neill MJ, Sims RA, Glazer AM, Shaffer CM, Crawford DM, Stricker T, Ye F, Wells Q, Stevenson LW, Michaud GF, Darbar D, Lubitz SA, Ellinor PT, Roden DM, Shoemaker MB.

JAMA Cardiol. 2021 Dec 1;6(12):1371-1379. doi: 10.1001/jamacardio.2021.3370.

PubMed [citation]

PMID:: 34495297
PMCID:: PMC8427496

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 Invitae, SCV000815619.4

#	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. ClinVar contains an entry for this variant (Variation ID: 567837). This premature translational stop signal has been observed in individual(s) with atrial fibrillation (PMID: 34495297). This variant is present in population databases (rs781802553, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Leu145Serfs*14) in the GJA5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 214 amino acid(s) of the GJA5 protein.

#	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: Mar 5, 2024

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