NM_003002.4(SDHD):c.320T>G (p.Leu107Arg) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Sep 21, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000986022.16

Allele description [Variation Report for NM_003002.4(SDHD):c.320T>G (p.Leu107Arg)]

NM_003002.4(SDHD):c.320T>G (p.Leu107Arg)

Gene:

SDHD:succinate dehydrogenase complex subunit D [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q23.1

Genomic location:

Preferred name:

NM_003002.4(SDHD):c.320T>G (p.Leu107Arg)

HGVS:

NC_000011.10:g.112094810T>G
NG_012337.3:g.12964T>G
NM_001276503.2:c.175T>G
NM_001276504.2:c.203T>G
NM_001276506.2:c.*18T>G
NM_003002.4:c.320T>GMANE SELECT
NP_001263432.1:p.Leu59Val
NP_001263433.1:p.Leu68Arg
NP_002993.1:p.Leu107Arg
LRG_9t1:c.320T>G
LRG_9:g.12964T>G
LRG_9p1:p.Leu107Arg
NC_000011.9:g.111965534T>G
NM_003002.2:c.320T>G
NM_003002.3:c.320T>G
NR_077060.2:n.409T>G

Protein change:

L107R

Links:

dbSNP: rs876658477

NCBI 1000 Genomes Browser:

rs876658477

Molecular consequence:

NM_001276506.2:c.*18T>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276503.2:c.175T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276504.2:c.203T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_003002.4:c.320T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_077060.2:n.409T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV001134819	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely pathogenic (Feb 27, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28977582, 26467025
SCV001471255	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Dec 7, 2019)	germline	clinical testing	Citation Link,
SCV004036869	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Sep 21, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001134819

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Likely pathogenic
(Feb 27, 2019)

germline

clinical testing

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

SCV001471255

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(Dec 7, 2019)

germline

clinical testing

Citation Link,

SCV004036869

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Sep 21, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Cardiac paraganglioma with a novel germline mutation of succinate dehydrogenase gene D.

Otani N, Sugano K, Inami S, Amano H, Arikawa T, Saito S, Imai K, Ushiama M, Yoshida T, Kimura N, Toyoda S, Inoue T.

Jpn J Clin Oncol. 2017 Dec 1;47(12):1193-1197. doi: 10.1093/jjco/hyx132.

PubMed [citation]

PMID:: 28977582

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134819.3

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

Description

The best available variant frequency is uninformative. Enriched in patients. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid.

#	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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001471255.1

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

Description

The SDHD c.320T>G; p.Leu107Arg variant (rs876658477), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 230274). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 107 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.320T>C; p.Leu107Pro) has been reported in a family with paraganglioma and is considered pathogenic (Otani 2017). However, given the lack of clinical and functional data, the significance of the p.Leu107Arg variant is uncertain at this time. References: Otani N et al. Cardiac paraganglioma with a novel germline mutation of succinate dehydrogenase gene D. Jpn J Clin Oncol. 2017 Dec 1;47(12):1193-1197.

#	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

From GeneDx, SCV004036869.1

#	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 supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34906457, 32035780)

#	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

Last Updated: Oct 26, 2024

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