NM_000116.5(TAFAZZIN):c.777+1G>A AND 3-Methylglutaconic aciduria type 2

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Feb 16, 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:: RCV003236876.3

Allele description [Variation Report for NM_000116.5(TAFAZZIN):c.777+1G>A]

NM_000116.5(TAFAZZIN):c.777+1G>A

Gene:

TAFAZZIN:tafazzin, phospholipid-lysophospholipid transacylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_000116.5(TAFAZZIN):c.777+1G>A

HGVS:

NC_000023.11:g.154420736G>A
NG_009634.2:g.14202G>A
NM_000116.5:c.777+1G>AMANE SELECT
NM_001303465.2:c.789+1G>A
NM_001410698.1:c.741+1G>A
NM_181311.4:c.687+1G>A
NM_181312.4:c.735+1G>A
NM_181313.4:c.645+1G>A
LRG_131t1:c.777+1G>A
LRG_131:g.14202G>A
NC_000023.10:g.153649075G>A
NC_000023.10:g.153649075G>A
NM_000116.4:c.777+1G>A

Links:

dbSNP: rs2068606932

NCBI 1000 Genomes Browser:

rs2068606932

Molecular consequence:

NM_000116.5:c.777+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001303465.2:c.789+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001410698.1:c.741+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_181311.4:c.687+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_181312.4:c.735+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_181313.4:c.645+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Observations:

Condition(s)

Name:: 3-Methylglutaconic aciduria type 2 (BTHS)
Synonyms:: Barth syndrome; 3-methylglutaconicaciduria type II; MGA type II; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010543; MedGen: C0574083; Orphanet: 111; OMIM: 302060

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003935916	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 15, 2020)	maternal, unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004299704	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Feb 16, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11238270, 17576681, 9536098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003935916

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 15, 2020)

maternal, unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004299704

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Feb 16, 2023)

germline

clinical testing

PubMed (4)
[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
not provided	maternal	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	no	1	not provided	not provided	1	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

Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome.

Ichida F, Tsubata S, Bowles KR, Haneda N, Uese K, Miyawaki T, Dreyer WJ, Messina J, Li H, Bowles NE, Towbin JA.

Circulation. 2001 Mar 6;103(9):1256-63.

PubMed [citation]

PMID:: 11238270

See all PubMed Citations (5)

Details of each submission

From Molecular Diagnostics Lab, Nemours Children's Health, Delaware, SCV003935916.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing (GTR000500853.3)	PubMed (1)
2	not provided	1	not provided	not provided	clinical testing (GTR000500853.3)	PubMed (1)
3	not provided	1	not provided	not provided	clinical testing (GTR000500853.3)	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	1	blood	not provided	(GTR000500853.3)	1	not provided	not provided	not provided
2	unknown	no	1	blood	not provided	(GTR000500853.3)	1	not provided	not provided	not provided
3	unknown	yes	1	blood	not provided	(GTR000500853.3)	1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004299704.1

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

Description

This sequence change affects a donor splice site in intron 10 of the TAZ gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Barth syndrome (PMID: 11238270; Invitae). ClinVar contains an entry for this variant (Variation ID: 928890). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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: Sep 29, 2024

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