Submissions for variant NM_004168.4(SDHA):c.1909-12_1909-11del

dbSNP: rs372662724

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000281629	SCV000457055	uncertain significance	Mitochondrial complex II deficiency, nuclear type 1	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000337728	SCV000457056	uncertain significance	Leigh syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000394391	SCV000457057	uncertain significance	Pheochromocytoma	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000483037	SCV000566911	likely benign	not specified	2017-12-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000492532	SCV000581184	likely benign	Hereditary cancer-predisposing syndrome	2013-12-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000483037	SCV001984293	likely benign	not specified	2020-07-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002061279	SCV002369814	likely benign	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-12-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000492532	SCV002527735	likely benign	Hereditary cancer-predisposing syndrome	2021-05-11	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000483037	SCV005090630	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001354980	SCV005879995	likely benign	not provided	2024-11-20	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354980	SCV001549724	likely benign	not provided		no assertion criteria provided	clinical testing	The SDHA c.1765-12_1765-11delCT variant was not identified in the literature, however the variant was identified in dbSNP (ID: rs886060516) as “With Uncertain significance allele”. In ClinVar, there were five submissions with conflicting interpretations of pathogenicity under the alias c.1909-12_1909-11delCT (NM_004168.3): likely benign (GeneDx and Ambry Genetics) and uncertain significance (3 submissions from Illumina). The associated conditions are: Pheochromocytoma, Leigh syndrome, Mitochondrial complex II deficiency, and Hereditary cancer-predisposing syndrome. The variant was also identified in LOVD 3.0 (benign), however it was not identified in the Cosmic or MutDB databases. The variant was identified in control databases in 34 of 279302 chromosomes at a frequency of 0.000122 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 9 of 24098 chromosomes (freq: 0.000374), Other in 2 of 7122 chromosomes (freq: 0.000281), European (Finnish) in 6 of 24800 chromosomes (freq: 0.000242), Ashkenazi Jewish in 1 of 10342 chromosomes (freq: 0.000097), European (non-Finnish) in 12 of 127414 chromosomes (freq: 0.000094), Latino in 3 of 35228 chromosomes (freq: 0.000085) and East Asian in 1 of 19696 chromosomes (freq: 0.000051), while the variant was not observed in the South Asian population. All four in silico splicing prediction programs (SpliceSiteFinder-like, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict an impact on splicing and MutationTaster has predicted the variant to be a polymorphism. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000483037	SCV001743715	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000483037	SCV001808888	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001354980	SCV001932854	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544660	SCV004798139	likely benign	SDHA-related disorder	2022-04-12	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).