NM_004168.4(SDHA):c.1273G>A (p.Val425Met) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001753700.5

Allele description [Variation Report for NM_004168.4(SDHA):c.1273G>A (p.Val425Met)]

NM_004168.4(SDHA):c.1273G>A (p.Val425Met)

Gene:

SDHA:succinate dehydrogenase complex flavoprotein subunit A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5p15.33

Genomic location:

Preferred name:

NM_004168.4(SDHA):c.1273G>A (p.Val425Met)

HGVS:

NC_000005.10:g.236440G>A
NG_012339.1:g.23200G>A
NM_001294332.2:c.1129G>A
NM_001330758.2:c.1273G>A
NM_004168.4:c.1273G>AMANE SELECT
NP_001281261.1:p.Val377Met
NP_001317687.1:p.Val425Met
NP_004159.2:p.Val425Met
LRG_315t1:c.1273G>A
LRG_315:g.23200G>A
LRG_315p1:p.Val425Met
NC_000005.9:g.236555G>A
NM_004168.2:c.1273G>A
NM_004168.3:c.1273G>A

Protein change:

V377M

Links:

dbSNP: rs201822097

NCBI 1000 Genomes Browser:

rs201822097

Molecular consequence:

NM_001294332.2:c.1129G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330758.2:c.1273G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004168.4:c.1273G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002005164	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (May 31, 2024)	germline	clinical testing	Citation Link,
SCV004220264	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jul 3, 2023)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29978154, 23666964, 28546994, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002005164

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(May 31, 2024)

germline

clinical testing

Citation Link,

SCV004220264

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Jul 3, 2023)

unknown

clinical testing

PubMed (4)
[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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Pathogenicity and Penetrance of Germline SDHA Variants in Pheochromocytoma and Paraganglioma (PPGL).

Maniam P, Zhou K, Lonergan M, Berg JN, Goudie DR, Newey PJ.

J Endocr Soc. 2018 Jul 1;2(7):806-816. doi: 10.1210/js.2018-00120.

PubMed [citation]

PMID:: 29978154
PMCID:: PMC6030830

A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma.

Rattenberry E, Vialard L, Yeung A, Bair H, McKay K, Jafri M, Canham N, Cole TR, Denes J, Hodgson SV, Irving R, Izatt L, Korbonits M, Kumar AV, Lalloo F, Morrison PJ, Woodward ER, Macdonald F, Wallis Y, Maher ER.

J Clin Endocrinol Metab. 2013 Jul;98(7):E1248-56. doi: 10.1210/jc.2013-1319. Epub 2013 May 10.

PubMed [citation]

PMID:: 23666964

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV002005164.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28500238, 23666964, 31721781, 28546994)

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004220264.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In the published literature, the variant has been reported in individuals with pheochromocytomas and paragangliomas (PMID: 23666964 (2013), 28546994 (2017)). The frequency of this variant in the general population, 0.00012 (4/34592 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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

Last Updated: Oct 8, 2024

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