NM_000116.5(TAFAZZIN):c.590G>A (p.Gly197Glu) AND 3-Methylglutaconic aciduria type 2

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jul 23, 2020
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:: RCV000035097.9

Allele description [Variation Report for NM_000116.5(TAFAZZIN):c.590G>A (p.Gly197Glu)]

NM_000116.5(TAFAZZIN):c.590G>A (p.Gly197Glu)

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.590G>A (p.Gly197Glu)

HGVS:

NC_000023.11:g.154420038G>A
NG_009634.2:g.13504G>A
NM_000116.5:c.590G>AMANE SELECT
NM_001303465.2:c.602G>A
NM_181311.4:c.500G>A
NM_181312.4:c.548G>A
NM_181313.4:c.458G>A
NP_000107.1:p.Gly197Glu
NP_001290394.1:p.Gly201Glu
NP_851828.1:p.Gly167Glu
NP_851829.1:p.Gly183Glu
NP_851830.1:p.Gly153Glu
LRG_131t1:c.590G>A
LRG_131:g.13504G>A
LRG_131p1:p.Gly197Glu
NC_000023.10:g.153648377G>A
NG_009634.1:g.13501G>A
NM_000116.3:c.590G>A
NR_024048.3:n.911G>A
c.590G>A

Protein change:

G153E

Links:

dbSNP: rs397515746

NCBI 1000 Genomes Browser:

rs397515746

Molecular consequence:

NM_000116.5:c.590G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001303465.2:c.602G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181311.4:c.500G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181312.4:c.548G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181313.4:c.458G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_024048.3:n.911G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000058737	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Jul 24, 2012)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9345098, 1719174, 24033266
SCV001577549	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 25, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9345098, 9382096, 23656970, 14654353, 28492532
SCV003935888	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 23, 2020)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9345058, 1719174, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000058737

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Jul 24, 2012)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001577549

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 25, 2020)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV003935888

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 23, 2020)

unknown

clinical testing

PubMed (3)
[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	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Mutation characterization and genotype-phenotype correlation in Barth syndrome.

Johnston J, Kelley RI, Feigenbaum A, Cox GF, Iyer GS, Funanage VL, Proujansky R.

Am J Hum Genet. 1997 Nov;61(5):1053-8.

PubMed [citation]

PMID:: 9345098
PMCID:: PMC1716030

See all PubMed Citations (9)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000058737.6

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

Description

The Gly197Glu variant in TAZ has been reported in one male infant with clinical features of Barth syndrome and a family history of disease that is consistent wi th X-linked inheritance (Kelley 1991, Johnston 1997). This variant has not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). This low frequency is consistent with a disease causing role but insufficient to esta blish this with confidence. Computational analyses (biochemical amino acid prope rties, conservation, PolyPhen2, and SIFT) suggest that this variant may impact t he protein, though this information is not predictive enough to determine pathog enicity. Finally, the majority of TAZ variants are pathogenic (www.barthsyndrome .org) and other variants at this position (Gly197Arg, Gly197Trp, Gly197Val) have been reported in individual's the Barth syndrome. In summary, this variant is l ikely to be pathogenic, though additional studies are required to fully establis h its clinical significance.

#	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		1	not provided	1	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001577549.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces glycine with glutamic acid at codon 197 of the TAZ protein (p.Gly197Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutatmic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Barth syndrome (PMID: 9345098). ClinVar contains an entry for this variant (Variation ID: 42264). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Not Available; PolyPhen-2: Probably Damaging; Align-GVGD: Not Available). This variant disrupts the p.Gly197 amino acid residue in TAZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9382096, 23656970, 14654353). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

From Molecular Diagnostics Lab, Nemours Children's Health, Delaware, SCV003935888.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	blood	not provided	(GTR000500853.3)	1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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