chr5-236598-TGG-T

Variant names:

• chr5-236598-TGG-T
• rs878854627
• ENST00000651543.1:n.*165_*165+1delGG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004168.4(SDHA):​c.1432_1432+1delGG​(p.Gly478ArgfsTer2) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,230 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SDHA NM_004168.4 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.58
• Publications: 4 publications found

Genes affected

ENSG00000286001 (HGNC:):

SDHA (HGNC:10680): (succinate dehydrogenase complex flavoprotein subunit A) This gene encodes a major catalytic subunit of succinate-ubiquinone oxidoreductase, a complex of the mitochondrial respiratory chain. The complex is composed of four nuclear-encoded subunits and is localized in the mitochondrial inner membrane. Mutations in this gene have been associated with a form of mitochondrial respiratory chain deficiency known as Leigh Syndrome. A pseudogene has been identified on chromosome 3q29. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

SDHA Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma/paraganglioma syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• neurodegeneration with ataxia and late-onset optic atrophy

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex II deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1GG

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-236598-TGG-T is Pathogenic according to our data. Variant chr5-236598-TGG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 239647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHA	NM_004168.4	c.1432_1432+1delGG	p.Gly478ArgfsTer2	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 10 of 15	ENST00000264932.11	NP_004159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000286001	ENST00000651543.1	n.*165_*165+1delGG		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 24			ENSP00000499215.1
SDHA	ENST00000264932.11	c.1432_1432+1delGG	p.Gly478ArgfsTer2	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 10 of 15	1	NM_004168.4	ENSP00000264932.6
ENSG00000286001	ENST00000651543.1	n.*165_*165+1delGG		splice_donor_variant, 3_prime_UTR_variant, intron_variant	Exon 9 of 24			ENSP00000499215.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251166 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000376 AC: 55 AN: 1461504 Hom.: 0 AF XY: 0.0000454 AC XY: 33 AN XY: 727066

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1111696

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Apr 09, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in patients with SDHA-related tumors in published literature (PMID: 29177515, 30877234, 34750850, 35053433); This variant is associated with the following publications: (PMID: 24781757, 22974104, 31263571, 16199547, 30877234, 29177515, 26556299, 34750850, 32782288, 35053433, 39133175) -

Nov 16, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHA c.1432_1432+1del (p.Gly478Glufs*17) variant alters the translational reading frame of the SDHA mRNA and causes the premature termination of SDHA protein synthesis. This variant has been reported in the published literature in individuals with head and neck PGL (PMIDs: 30877234 (2019), 29177515 (2018)), retroperitoneal PGL (PMID: 28384794 (2017)), and thoracic PGL (PMID: 34750850 (2022)). Additionally, the variant has been reported in individuals with bile duct cancer (PMID: 31263571 (2019)) and renal cancer (PMID: 32782288 (2020)). The frequency of this variant in the general population, 0.000004 (1/251166 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Pheochromocytoma/paraganglioma syndrome 5 Pathogenic:1

Feb 08, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -

Dilated cardiomyopathy 1GG Pathogenic:1

Dec 07, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in the deletion of part of exon 10 (c.1432_1432+1del) of the SDHA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHA are known to be pathogenic (PMID: 22974104, 24781757). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has been observed in individuals with breast cancer, paraganglioma-pheochromocytoma syndrome, and/or renal cancer (PMID: 29177515, 30877234, 32782288, 34750850; internal data). ClinVar contains an entry for this variant (Variation ID: 239647). Studies have shown that this variant is associated with inconclusive levels of altered splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -

Paraganglioma;C0031511:Pheochromocytoma Pathogenic:1

Jul 10, 2020

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in a male proband with phaeochromocytoma and lung nodule. The variant has previously been reported in the literature, including in a male with glomus jugulare tumour (PMID: 29177515); a male with retroperitoneal paraganglioma (PMID 28384794); a male with gallbladder paraganglioma, pancreatic neuroendocrine tumour and metastatic prostate cancer (PMID: 32534711); and a female with thoracic paraganglioma (PMCID: PMC7209502) (PS4_moderate). The variant is absent from population database gnomAD (PM2_supporting) and is predicted to result in loss of protein function (PVS1_very_strong). Data included in classification: Prevalence in affected versus controls GT-AG 1,2 splice site variant predicted to result in loss of protein function Data not included in classification: Functional data -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 24, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1432_1432+1delGG pathogenic mutation spans the coding exon 10/intron 10 boundary of the SDHA gene and results from the deletion of 2 nucleotides at nucleotide positions c.1432 and c.1432+1. The deleted region includes the last nucleotide and canonical donor site, which is highly conserved in available vertebrate species. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with SDHA-related disease (Ambry internal data; Bausch B et al. JAMA Oncol 2017 Sep;3(9):1204-1212; van der Tuin K et al. J Clin Endocrinol Metab 2018 02;103(2):438-445). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Neurodegeneration with ataxia and late-onset optic atrophy Pathogenic:1

Dec 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SDHA c.1432_1432+1delGG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251166 control chromosomes (gnomAD). c.1432_1432+1delGG has been reported in the literature in individuals affected with paraganglioma or cancers including renal cancer (van der Tuin_2018, Ben Aim_2019, Hartman_2020, Parisien-La Salle_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29177515, 30877234, 34750850, 32782288). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dilated cardiomyopathy 1GG;C3279992:Pheochromocytoma/paraganglioma syndrome 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1

Jan 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs878854627; hg19: chr5-236713; COSMIC: COSV53775737;