Submissions for variant NC_012920.1(MT-ATP6):m.8993T>G

dbSNP: rs199476133

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV000495419	SCV001736753	pathogenic	Mitochondrial disease	2021-03-22	reviewed by expert panel	curation	The m.8993T>G (p.L156R) variant in MT-ATP6 has been reported in >16 individuals with primary mitochondrial disease (PS4; PMIDs: 2137962, 8250532, 8240109, 7605802, 8505474, 9221962, 10208283, 16525806, 10660580). There are several reports of de novo occurrences of this variant (PM6_strong, PMIDs: 29602698, 27450679, 12134275). This variant is located at the same amino acid position as another well-known pathogenic variant, m.8993T>C (p.L156P) (PM5). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 2137962, 1436530, 1550128, 8095070, 9221962). This variant is absent in population databases after removing known patients with mitochondrial disease (PM2_supporting). In silico tools (APOGEE) predict this variant to be pathogenic (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 14998933, 8078883, 19875463). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on March 22, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM2_supporting, PM5, PM6_strong, PP1_moderate, PP3).
Baylor Genetics	RCV000191106	SCV000245508	pathogenic	Cerebellar ataxia	2014-11-06	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory homoplasmic in a 22-year-old female with ataxia, abnormal movements - inherited from a heteroplasmic mother
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224643	SCV000280809	pathogenic	not provided	2014-07-15	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414771	SCV000493050	pathogenic	Hypertelorism; Bilateral cleft lip and palate; Low-set ears; Premature birth; Wide intermamillary distance; Hypoplasia of scrotum; Postaxial hand polydactyly; Camptodactyly of finger	2014-04-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224643	SCV000885721	pathogenic	not provided	2018-05-24	criteria provided, single submitter	clinical testing	The m.8993T>G affects the MT-ATP6 gene, and this well-studied variant accounts of the majority of patients diagnosed with Mitochondrial DNA (mtDNA)-associated Leigh syndrome and NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa; see GeneReviews: NBK1173).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000010274	SCV000997424	pathogenic	NARP syndrome	2019-10-17	criteria provided, single submitter	clinical testing	The NC_012920.1:m.8993T>G (YP_003024031.1:p.Leu156Arg) variant in MTATP6 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PS3
Kids Research, The Children's Hospital at Westmead	RCV000754646	SCV001244727	pathogenic	Mitochondrial complex 5 (ATP synthase) deficiency, mitochondrial type 1		criteria provided, single submitter	research
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376274	SCV001573357	pathogenic	Rod-cone dystrophy	2021-04-08	criteria provided, single submitter	research	The MT-ATP6 c.467T>G variant was identified in an individual with retinitis pigmentosa with a presumed mitochondrial inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PS4, PP1. Based on this evidence we have classified this variant as Pathogenic.
Genomics England Pilot Project, Genomics England	RCV001542706	SCV001760537	likely pathogenic	Leber optic atrophy		criteria provided, single submitter	clinical testing
Mendelics	RCV001542706	SCV002517649	pathogenic	Leber optic atrophy	2022-05-04	criteria provided, single submitter	clinical testing
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV002285006	SCV002574882	pathogenic	not specified	2022-09-22	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000754646	SCV002581009	pathogenic	Mitochondrial complex 5 (ATP synthase) deficiency, mitochondrial type 1	2022-07-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000495419	SCV004014679	pathogenic	Mitochondrial disease	2023-03-15	criteria provided, single submitter	clinical testing	The MT-ATP6 c.467T>G (p.Leu156Arg) variant, also known as m.8993T>G variant, is a mitochondrial missense variant that results in the substitution of leucine at amino acid position 156 with arginine. Across a selection of the available literature, the c.467T>G variant has been identified in at least 16 unrelated individuals with primary mitochondrial disease (PMID: 2137962; PMID: 8250532; PMID: 9221962). Clinical features and onset of symptoms vary depending on the levels of heteroplasmy, with a direct correlation between levels of heteroplasmy and severity of symptoms. In general, affected individuals show 85-95% heteroplasmy in blood and other tissues. While the variant has been shown to segregate with the disorder in multiple families, there are several reports of the variant in a de novo state as well (PMID: 9221962; PMID: 27450679; PMID: 29602698). Another variant at the same amino acid position, c.467T>C (p.Leu156Pro), is also a well-known pathogenic variant for primary mitochondrial disease. The c.467T>G variant is not found in version 3.1.2 of the Genome Aggregation Database. Cybrid cell lines with this variant show ATP synthesis defects (PMID: 19875463). Based on the available evidence, the c.467T>G (p.Leu156Arg) variant is classified as pathogenic for primary mitochondrial disease.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000010273	SCV004100787	pathogenic	Leigh syndrome	2024-06-16	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PM6_STR,PM5,PP1_MOD,PS3_SUP,PM2_SUP,PP3
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000010273	SCV004171237	pathogenic	Leigh syndrome	2023-11-30	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000224643	SCV005199232	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000754646	SCV000030497	pathogenic	Mitochondrial complex 5 (ATP synthase) deficiency, mitochondrial type 1	2009-08-01	no assertion criteria provided	literature only
OMIM	RCV000010274	SCV000030498	pathogenic	NARP syndrome	2009-08-01	no assertion criteria provided	literature only
GeneReviews	RCV000010273	SCV000188893	not provided	Leigh syndrome		no assertion provided	literature only
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000010273	SCV000492530	pathogenic	Leigh syndrome	2016-09-29	no assertion criteria provided	clinical testing
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000495419	SCV000577899	pathogenic	Mitochondrial disease	2017-05-22	no assertion criteria provided	clinical testing
Solve-RD Consortium	RCV000010274	SCV005199969	likely pathogenic	NARP syndrome	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team