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NM_003000.3(SDHB):c.221A>C (p.Asp74Ala) AND not provided

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Jun 14, 2022
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:
RCV001551663.16

Allele description [Variation Report for NM_003000.3(SDHB):c.221A>C (p.Asp74Ala)]

NM_003000.3(SDHB):c.221A>C (p.Asp74Ala)

Gene:
SDHB:succinate dehydrogenase complex iron sulfur subunit B [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p36.13
Genomic location:
Preferred name:
NM_003000.3(SDHB):c.221A>C (p.Asp74Ala)
HGVS:
  • NC_000001.11:g.17033125T>G
  • NG_012340.1:g.26046A>C
  • NM_003000.3:c.221A>CMANE SELECT
  • NP_002991.2:p.Asp74Ala
  • NP_002991.2:p.Asp74Ala
  • LRG_316t1:c.221A>C
  • LRG_316:g.26046A>C
  • LRG_316p1:p.Asp74Ala
  • NC_000001.10:g.17359620T>G
  • NM_003000.2:c.221A>C
Protein change:
D74A
Links:
dbSNP: rs876658713
NCBI 1000 Genomes Browser:
rs876658713
Molecular consequence:
  • NM_003000.3:c.221A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000605079ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)
Likely pathogenic
(Feb 11, 2022)
germlineclinical testing

Citation Link,

SCV001772221GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Pathogenic
(Jun 14, 2022)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000605079.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The SDHB c.221A>C; p.Asp74Ala variant (rs876658713) is reported in the literature in an individual affected with hereditary paraganglioma-pheochromocytoma syndrome (Greenberg 2020). This variant has also been observed in multiple patients affected with paraganglioma and renal cell carcinoma including SDH-deficient tumors at ARUP and other laboratories (external communications). This variant is also reported in ClinVar (Variation ID: 230694), but is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The aspartate at codon 74 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.939). Based on available information, this variant is considered to be likely pathogenic. References: Greenberg SE et al. Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome. Genet Med. 2020 Dec;22(12):2101-2107. PMID: 32741965.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From GeneDx, SCV001772221.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals undergoing screening for Hereditary PGL/PCC syndrome in published literature (Greenberg 2020); This variant is associated with the following publications: (PMID: 32741965)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024