Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001237758 | SCV001410532 | pathogenic | Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome | 2024-01-16 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 416 of the TRNT1 protein (p.Lys416Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of TRNT1-related conditions (PMID: 25193871, 29358286, 33332575, 33646446; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 963695). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TRNT1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect TRNT1 function (PMID: 25193871). For these reasons, this variant has been classified as Pathogenic. |
| Institute for Genomic Medicine |
RCV001249658 | SCV001423622 | likely pathogenic | Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome; Retinitis pigmentosa and erythrocytic microcytosis | 2018-10-31 | criteria provided, single submitter | clinical testing | [ACMG/AMP: PM2, PM3, PM_PS3] This alteration is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic variant [PM3]. |
| Molecular Genetics, |
RCV001237758 | SCV002498623 | likely pathogenic | Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome | 2022-04-05 | criteria provided, single submitter | clinical testing | This sequence change in TRNT1 is predicted to replace lysine with glutamic acid at codon 416, p.(Lys416Glu). The lysine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in a helical region with an annotated function. There is a small physicochemical difference between lysine and glutamic acid. The highest population minor allele frequency in gnomAD v2.1 is 0.01% (2/19,944 alleles) in the East Asian population, which is lower than the credible allele frequency for a recessive condition. This variant has been detected in at least six individuals (from five families) with periodic fevers, developmental delay, and varying degrees of anaemia with B-cell immunodeficiency. Of those individuals, five were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and four of those were confirmed in trans by parental/family testing (PMID: 25193871, 29358286, 32371413, 33332575; Doi: 10.51271/jpea-2021-0110). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict benign). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PM2_Supporting, PP1. |