Submissions for variant NM_004168.4(SDHA):c.378del (p.Thr126_Val127insTer)

dbSNP: rs1553997617

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000539370	SCV000651339	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-08-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val127*) in the SDHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 472290). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001021144	SCV001182723	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-25	criteria provided, single submitter	clinical testing	The c.378delC pathogenic mutation (also known as p.V127*), located in coding exon 4 of the SDHA gene, results from a deletion of one nucleotide at nucleotide position 378. This changes the amino acid from a valine to a stop codon within coding exon 4. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV004538051	SCV004113532	pathogenic	SDHA-related disorder	2023-01-11	criteria provided, single submitter	clinical testing	The SDHA c.378delC variant is predicted to result in premature protein termination (p.Val127*). To our knowledge, this variant has not been reported in a patients with SDHA-related disorders. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in SDHA are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003476304	SCV004200628	likely pathogenic	Dilated cardiomyopathy 1GG	2023-06-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003151099	SCV004220303	pathogenic	not provided	2023-06-29	criteria provided, single submitter	clinical testing	The SDHA c.378del (p.Val127*) variant causes the premature termination of SDHA protein synthesis. This variant has not been reported in individuals with SDHA-related conditions in the published literature. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. "
Myriad Genetics, Inc.	RCV004024205	SCV004933612	pathogenic	Paragangliomas 5	2024-02-07	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005367399	SCV005914774	pathogenic	Leigh syndrome	2024-11-20	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV003151099	SCV003840033	likely pathogenic	not provided	2022-07-22	no assertion criteria provided	clinical testing	DNA sequence analysis of the SDHA gene demonstrated a sequence change, c.378del, which results in the creation of a premature stop codon at amino acid position 127,p.Val127*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated SDHA protein with potentially abnormal function. This sequence change has not been described in population databases such as ExAC and gnomAD. Loss-of-function variants in SDHA have been reported to be pathogenic (PMID: 22974104, 24781757). These collective evidences indicate that this sequence change is likely pathogenic.