NM_017841.4(SDHAF2):c.315T>A (p.Tyr105Ter) AND Paragangliomas 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 12, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003495225.1

Allele description [Variation Report for NM_017841.4(SDHAF2):c.315T>A (p.Tyr105Ter)]

NM_017841.4(SDHAF2):c.315T>A (p.Tyr105Ter)

Gene:

SDHAF2:succinate dehydrogenase complex assembly factor 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q12.2

Genomic location:

Preferred name:

NM_017841.4(SDHAF2):c.315T>A (p.Tyr105Ter)

HGVS:

NC_000011.10:g.61438058T>A
NG_023393.1:g.12934T>A
NM_017841.4:c.315T>AMANE SELECT
NP_060311.1:p.Tyr105Ter
LRG_519t1:c.315T>A
LRG_519:g.12934T>A
NC_000011.9:g.61205530T>A
NM_017841.2:c.315T>A

Protein change:

Y105*

Links:

dbSNP: rs750979204

NCBI 1000 Genomes Browser:

rs750979204

Molecular consequence:

NM_017841.4:c.315T>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Paragangliomas 2 (PPGL2)
Synonyms:: Glomus tumors, familial, 2; SDHAF2-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome (Paragangliomas 2); PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 2
Identifiers:: MONDO: MONDO:0011121; MedGen: C1866552; Orphanet: 29072; OMIM: 601650

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004362266	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 12, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32887801, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004362266

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 12, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The roles of SDHAF2 and dicarboxylate in covalent flavinylation of SDHA, the human complex II flavoprotein.

Sharma P, Maklashina E, Cecchini G, Iverson TM.

Proc Natl Acad Sci U S A. 2020 Sep 22;117(38):23548-23556. doi: 10.1073/pnas.2007391117. Epub 2020 Sep 4.

PubMed [citation]

PMID:: 32887801
PMCID:: PMC7519310

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV004362266.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant changes 1 nucleotide in exon 3 (4 total exons) of the SDHAF2 gene, creating a premature translation stop signal. This variant is close to the NMD border region (50-55 nucleotides upstream of the 3' end of the penultimate exon), but is expected to result in an absent or non-functional protein product. This variant removes the C-terminal 62 amino acids of SDHAF2. Deletion of the C-terminal 15 residues of SDHAF2 has been shown to abolish binding to and flavinylation of SDHA (PMID: 32887801). To our knowledge, this variant has not been reported in individuals affected with SDHAF2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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