Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000283338 | SCV000329698 | pathogenic | not provided | 2019-08-13 | criteria provided, single submitter | clinical testing | 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) |
| Invitae | RCV000029171 | SCV000635075 | pathogenic | 3-Methylglutaconic aciduria type 2 | 2023-12-09 | criteria provided, single submitter | clinical testing | 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. |
| Molecular Diagnostics Lab, |
RCV000029171 | SCV003935892 | likely pathogenic | 3-Methylglutaconic aciduria type 2 | 2020-07-21 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000029171 | SCV000051816 | pathogenic | 3-Methylglutaconic aciduria type 2 | 1997-10-01 | no assertion criteria provided | literature only | |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000283338 | SCV000925223 | pathogenic | not provided | 2017-02-08 | no assertion criteria provided | provider interpretation | 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 improved. Of note, this younger brother had a normal ultrasound at both 16 and 35 weeks of pregnancy. Neither brother had recurrent infections or neutropenia; they had an unrevealing metabolic workup and there was no mention of skeletal myopathy. The parents in this family had a son previously who died at 8 months, within 4 days of a hospitalization for "pneumonia". The p.Gly240Arg variant was present in both of the older brothers. The mother was not tested. The glycine at codon 240 is conserved across species, as are neighboring amino acids. There is no variation at codon listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in ExAC |