NM_000116.5(TAFAZZIN):c.763G>A (p.Glu255Lys) AND 3-Methylglutaconic aciduria type 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 4, 2024
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:: RCV000817139.8

Allele description [Variation Report for NM_000116.5(TAFAZZIN):c.763G>A (p.Glu255Lys)]

NM_000116.5(TAFAZZIN):c.763G>A (p.Glu255Lys)

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.763G>A (p.Glu255Lys)

Other names:

p.E255K:GAG>AAG

HGVS:

NC_000023.11:g.154420721G>A
NG_009634.2:g.14187G>A
NM_000116.5:c.763G>AMANE SELECT
NM_001303465.2:c.775G>A
NM_181311.4:c.673G>A
NM_181312.4:c.721G>A
NM_181313.4:c.631G>A
NP_000107.1:p.Glu255Lys
NP_001290394.1:p.Glu259Lys
NP_851828.1:p.Glu225Lys
NP_851829.1:p.Glu241Lys
NP_851830.1:p.Glu211Lys
LRG_131t1:c.763G>A
LRG_131:g.14187G>A
LRG_131p1:p.Glu255Lys
NC_000023.10:g.153649060G>A
NG_009634.1:g.14184G>A
NM_000116.3:c.763G>A
NM_000116.4:c.763G>A
NR_024048.3:n.1084G>A

Protein change:

E211K

Links:

dbSNP: rs782498694

NCBI 1000 Genomes Browser:

rs782498694

Molecular consequence:

NM_000116.5:c.763G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001303465.2:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181311.4:c.673G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181312.4:c.721G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181313.4:c.631G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_024048.3:n.1084G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000957684	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 4, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29089047, 28492532
SCV002768850	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 6, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29089047, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000957684

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 4, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002768850

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 6, 2021)

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
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns.

Li AH, Hanchard NA, Furthner D, Fernbach S, Azamian M, Nicosia A, Rosenfeld J, Muzny D, D'Alessandro LCA, Morris S, Jhangiani S, Parekh DR, Franklin WJ, Lewin M, Towbin JA, Penny DJ, Fraser CD, Martin JF, Eng C, Lupski JR, Gibbs RA, Boerwinkle E, et al.

Genome Med. 2017 Oct 31;9(1):95. doi: 10.1186/s13073-017-0482-5.

PubMed [citation]

PMID:: 29089047
PMCID:: PMC5664429

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000957684.5

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

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 255 of the TAZ protein (p.Glu255Lys). This variant is present in population databases (rs782498694, gnomAD 0.006%). This missense change has been observed in individual(s) with a cardiovascular malformation (PMID: 29089047). ClinVar contains an entry for this variant (Variation ID: 202096). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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.

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768850.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Barth syndrome (MIM#302060). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 2 heterozygotes, 0 homozygotes, 2 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated LPLAT_AGPAT-like domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as a VUS for 3-Methylglutaconic aciduria type 2 (ClinVar) and was also regarded as a candidate variant for left-side lesion (LSL) based on in silico studies (PMID: 29089047). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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: Sep 29, 2024

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