Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003985426 | SCV004801740 | likely benign | Mitochondrial disease | 2023-08-22 | reviewed by expert panel | curation | The m.13528A>G (p.T398A) variant in MT-ND5 gene has been reported in six unrelated families to date. The proband in one of these families was subsequently found to have a homozygous pathogenic variant in POLG (PMID: 17940288, BP5). Four other probands had features consistent with primary mitochondrial disease however comprehensive analysis of other genetic etiologies was not performed. Three of these individuals had with features consistent with Leber Hereditary Optic Neuropathy (LHON; PMIDs: 11102991, 22589247). The fourth proband had features consistent with Leigh syndrome spectrum disorder (PMID: 19103152). There is also a report of a family with several siblings with autism spectrum disorder having this variant (PMID: 28419775). However, while this variant is present in these families, it is present at fairly high frequency in the general population. The frequency in the MITOMAP GenBank sequences is 75/61,168 (0.123%). The frequency in the Helix dataset is 516/195,983 (0.263%) homoplasmic occurrences in addition to four heteroplasmic occurrences. The frequency in gnomAD v3.1.2 is 118/56,421 (0.209%) homoplasmic occurrences in addition to three heteroplasmic occurrences. In all three population databases, this variant is seen in individuals from different haplogroups. Cybrid studies support a deleterious effect however it is not clear if this effect is related to the variant or other factors such as mitochondrial DNA content and/or haplogroup effects (PMIDs: 17940288, 22589247). The computational predictor APOGEE gives a consensus rating of neutral with a score of 0.45 (Min=0, Max=1), which predicts no damaging effect on gene function (BP4). In summary, this variant meets criteria to be classified as likely benign for primary mitochondrial disease inherited in a mitochondrial manner. We note that two experts on this panel felt uncertain significance was a more appropriate classification given the cybrid studies however the majority (four) agreed with likely benign. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4, BP5. |
| ARUP Laboratories, |
RCV000756359 | SCV000884149 | uncertain significance | not provided | 2017-11-17 | criteria provided, single submitter | clinical testing | The m.13528A>G variant (rs55882959) has been described in the literature as both a pathogenic and benign variant. It was originally observed in two unrelated patients diagnosed with Leber hereditary optic neuropathy (LHON) and was not found in 125 healthy controls (Batandier 2000). It has also been reported in patients diagnosed with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS, McKenzie 2007) and in a different proband with LHON (Petruzzella 2012). Conversely, this variant has also been associated (along with g.13565C>T) with the U4b1b haplogroup (Herrnstadt 2002, Malyarchuk 2008), and is therefore present in presumably healthy individuals. In total, it is found 38 times over 6 total haplogroups in MITOMAP. Based on the available evidence, the m.13528A>G variant is unlikely to be a primary LHON variant; however, a contributory role for this variant to LHON expression cannot be excluded. |
| Wong Mito Lab, |
RCV000854944 | SCV000997991 | benign | Leigh syndrome | 2019-10-17 | criteria provided, single submitter | clinical testing | The NC_012920.1:m.13528A>G (YP_003024036.1:p.Thr398Ala) variant in MTND5 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2, BP4 |
| Gene |
RCV003334007 | SCV004042641 | not provided | MELAS syndrome | no assertion provided | literature only |