NM_003002.4(SDHD):c.118A>C (p.Ile40Leu) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 13, 2024
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:: RCV003103746.11

Allele description [Variation Report for NM_003002.4(SDHD):c.118A>C (p.Ile40Leu)]

NM_003002.4(SDHD):c.118A>C (p.Ile40Leu)

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.118A>C (p.Ile40Leu)

HGVS:

NC_000011.10:g.112087922A>C
NG_012337.3:g.6076A>C
NG_033145.1:g.3877T>G
NM_001276503.2:c.118A>C
NM_001276504.2:c.53-945A>C
NM_001276506.2:c.118A>C
NM_003002.4:c.118A>CMANE SELECT
NP_001263432.1:p.Ile40Leu
NP_001263435.1:p.Ile40Leu
NP_002993.1:p.Ile40Leu
LRG_9t1:c.118A>C
LRG_9:g.6076A>C
LRG_9p1:p.Ile40Leu
NC_000011.9:g.111958646A>C
NM_001276506.1:c.118A>C
NM_003002.2:c.118A>C
NM_003002.3:c.118A>C
NR_077060.2:n.153A>C

Protein change:

I40L

Links:

dbSNP: rs146276662

NCBI 1000 Genomes Browser:

rs146276662

Molecular consequence:

NM_001276504.2:c.53-945A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001276503.2:c.118A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276506.2:c.118A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_003002.4:c.118A>C - missense variant - [Sequence Ontology: SO:0001583]
NR_077060.2:n.153A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Carney-Stratakis syndrome
Synonyms:: Paraganglioma and gastric stromal sarcoma; Paraganglioma and gastrointestinal stromal tumor; Paraganglioma and GIST; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011740; MedGen: C1847319; Orphanet: 97286; OMIM: 606864

Name:: Pheochromocytoma
Synonyms:: Chromaffinoma; Chromaffin paraganglioma; Chromaffin tumor; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008233; MedGen: C0031511; Orphanet: 29072; OMIM: 171300; Human Phenotype Ontology: HP:0002666

Name:: Paragangliomas with sensorineural hearing loss (PGL1)
Identifiers:: MedGen: C1868633

Name:: Cowden syndrome 3 (CWS3)
Identifiers:: MONDO: MONDO:0014045; MedGen: CN166604; Orphanet: 201

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000287813	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 13, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22829200, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000287813

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 13, 2024)

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

Vitamin E protects against lipid peroxidation and rescues tumorigenic phenotypes in cowden/cowden-like patient-derived lymphoblast cells with germline SDHx variants.

Ni Y, Eng C.

Clin Cancer Res. 2012 Sep 15;18(18):4954-61. Epub 2012 Jul 24.

PubMed [citation]

PMID:: 22829200
PMCID:: PMC3445717

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000287813.10

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

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 40 of the SDHD protein (p.Ile40Leu). This variant is present in population databases (rs146276662, gnomAD 0.005%). This missense change has been observed in individual(s) with Cowden or Cowden-like syndrome (PMID: 22829200). ClinVar contains an entry for this variant (Variation ID: 218581). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHD protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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