rs387907218

Positions:

• chrX-154420676-G-A
• chrX-154420676-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000116.5(TAFAZZIN):​c.718G>A​(p.Gly240Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,186 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: TAFAZZIN NM_000116.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.50

Genes affected

TAFAZZIN (HGNC:11577): (tafazzin, phospholipid-lysophospholipid transacylase) This gene encodes a protein that is expressed at high levels in cardiac and skeletal muscle. Mutations in this gene have been associated with a number of clinical disorders including Barth syndrome, dilated cardiomyopathy (DCM), hypertrophic DCM, endocardial fibroelastosis, and left ventricular noncompaction (LVNC). Multiple transcript variants encoding different isoforms have been described. A long form and a short form of each of these isoforms is produced; the short form lacks a hydrophobic leader sequence and may exist as a cytoplasmic protein rather than being membrane-bound. Other alternatively spliced transcripts have been described but the full-length nature of all these transcripts is not known. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a topological_domain Mitochondrial intermembrane (size 226) in uniprot entity TAZ_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000116.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-154420676-G-A is Pathogenic according to our data. Variant chrX-154420676-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154420676-G-A is described in Lovd as [Likely_pathogenic]. Variant chrX-154420676-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAFAZZIN	NM_000116.5	c.718G>A	p.Gly240Arg	missense_variant	10/11	ENST00000601016.6	NP_000107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAFAZZIN	ENST00000601016.6	c.718G>A	p.Gly240Arg	missense_variant	10/11	1	NM_000116.5	ENSP00000469981

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098186 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363548

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-Methylglutaconic aciduria type 2 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 21, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 240 of the TAZ protein (p.Gly240Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Barth syndrome co-segregating with disease in an X-linked fashion (PMID: 4685904, 9382096, 11896212, 23345479). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 35505). 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 disruptive. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1997	- -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 08, 2017	Given the numerous case reports, moderate segregation data and absence from control populations, we consider this variant very likely disease-causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 5 unrelated cases of infantile, "isolated" dilated cardiomyopathy (not including this patient's family). In total, it is present in 11 individuals with infantile, "isolated" dilated cardiomyopathy, and 7 female obligate carriers from 6 families. There is strong case data for this variant (reviewed below). TAZ is located on the X chromosome (Xq28) and has 11 exons and multiple isoforms. Tafazzins, the proteins encoded by TAZ, are involved in cardiolipin biosynthesis and remodeling. The species of cardiolipin that tafazzin creates is abundant in highly oxidative tissues, such as the heart. Disruptive variants cause malformed mitochondrial membranes. Disease-causing variants in the TAZ gene cause Barth syndrome, a multi-systemic disorder with cardiac manifestations, (cyclic) neutropenia, increased urinary excretion of 3-methylglutaconic acid and skeletal myopathy. Cardiac manifestations include dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), endocardial fibroelastosis, left ventricular non-compaction (LVNC), ventricular arrhythmia, sudden cardiac arrest or death, prolonged QTc and heart transplant. Not all boys with Barth syndrome have all of the above features. Due to TAZ's location on the X chromosome, males with a pathogenic variant in TAZ are at higher risk of developing Barth syndrome than females. There are a couple of case reports of females developing Barth syndrome, but that is due to extreme skewing of the expression of the X chromosome (one case) and structural/loss of function variation in another female. This variant is present in ClinVar. It was submitted by GeneDx and LMM, who also call this variant pathogenic. D'Adamo and colleagues (1997) sequenced a large family with X-linked infantile, fatal, "isolated" dilated cardiomyopathy. Four males died within 3-4 months of life due to heart failure. Another male developed heart failure at 5 weeks of age, survived, and at the time of publication, was doing well at 25 years old. This variant, p.Gly240Arg, was present in four of these affected males as well as in one female obligate carrier. D'Adamo and colleagues (1997) sequenced another large family, first reported by Lindenbaum et al (1973) with X-linked endocardial fibroelastosis. Four males died unexpectedly and early from "acute bronchitis," "bronchopneumonia," and "natural causes (convulsions). The p.Gly240Arg variant was present in 3 obligate female carriers. No probands were available to test. Bissler and colleagues (2002) sequenced the TAZ gene in two male cousins with "isolated" dilated cardiomyopathy. At the time of publication, the boys were alive at 9 years old and 5 years old. It is not clear when they presented with dilated cardiomyopathy. They had 17 male relatives in three previous generations that died of "presumed cardiomyopathy). They found that these boys' mitochondria aggregated and were very large. Furthermore, the mitochondrial cristae were closely packed together and disarrayed. Man and colleagues (2013), sequenced the TAZ gene in two Chinese brothers with dilated cardiomyopathy. The oldest brother presented with perioral cyanosis on day 2 of life, and an echo showed left ventricular hypertrophy and dilatation. Myocarditis was ruled out. His left ventricular function progressively declined, with a depressed ejection fraction and global hypokinesia. At the time of publication, he remains stable on digoxin and captopril. His younger brother was noted to have cardiomegaly during a hospitalization for bronchiolitis at 5 months of age, and an echocardiogram showed a dilated left ventricle with impaired contractility. He was admitted to the hospital and his cardiac function im -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2019	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 4685904, 12468278, 25941633, 20474083, 9382096, 29071820, 11896212, 30384889) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;.;.;D;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-7.5	.;.;.;.;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	.;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.92
MutPred		0.93		.;.;.;Gain of MoRF binding (P = 0.007);.;
MVP		1.0
ClinPred		1.0	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs387907218; hg19: chrX-153649015; COSMIC: COSV54795894; COSMIC: COSV54795894;