NM_003002.4(SDHD):c.445_448dup (p.Cys150fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Sep 5, 2023
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:: RCV002257334.4

Allele description [Variation Report for NM_003002.4(SDHD):c.445_448dup (p.Cys150fs)]

NM_003002.4(SDHD):c.445_448dup (p.Cys150fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

11q23.1

Genomic location:

Preferred name:

NM_003002.4(SDHD):c.445_448dup (p.Cys150fs)

HGVS:

NC_000011.10:g.112094935_112094938dup
NG_012337.3:g.13089_13092dup
NM_001276503.2:c.*42_*45dup
NM_001276504.2:c.328_331dup
NM_001276506.2:c.*143_*146dup
NM_003002.4:c.445_448dupMANE SELECT
NP_001263433.1:p.Cys111fs
NP_002993.1:p.Cys150fs
LRG_9t1:c.445_448dup
LRG_9:g.13089_13092dup
LRG_9p1:p.Cys150fs
NC_000011.9:g.111965659_111965662dup
NM_003002.2:c.445_448dupATCT
NR_077060.2:n.534_537dup

Protein change:

C111fs

Links:

dbSNP: rs2135277783

NCBI 1000 Genomes Browser:

rs2135277783

Molecular consequence:

NM_001276503.2:c.*42_*45dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276506.2:c.*143_*146dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276504.2:c.328_331dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_003002.4:c.445_448dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_077060.2:n.534_537dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

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Mus musculus mRNA for synaptotagumin III, complete cds
Mus musculus mRNA for synaptotagumin III, complete cds
gi|1321654|dbj|D45858.1|MUSMSYTIII

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002535341	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely pathogenic (Sep 15, 2021)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 25547508, 22290790, 19027316 Citation Link,
SCV004051961	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 5, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19027316, 22241717, 22290790, 25547508 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002535341

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Likely pathogenic
(Sep 15, 2021)

germline

curation

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004051961

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 5, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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, curation

Citations

PubMed

Pigmented 'black' cardiac paraganglioma in a patient with a novel germ-line SDHD mutation.

Petramala L, Cotesta D, Filetti S, Letizia C.

Eur J Cardiothorac Surg. 2009 Jan;35(1):189. doi: 10.1016/j.ejcts.2008.10.007. Epub 2008 Nov 21. No abstract available.

PubMed [citation]

PMID:: 19027316

Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients.

Piccini V, Rapizzi E, Bacca A, Di Trapani G, Pulli R, Giachè V, Zampetti B, Lucci-Cordisco E, Canu L, Corsini E, Faggiano A, Deiana L, Carrara D, Tantardini V, Mariotti S, Ambrosio MR, Zatelli MC, Parenti G, Colao A, Pratesi C, Bernini G, Ercolino T, et al.

Endocr Relat Cancer. 2012 Apr 10;19(2):149-55. doi: 10.1530/ERC-11-0369. Print 2012 Apr.

PubMed [citation]

PMID:: 22241717

See all PubMed Citations (4)

Details of each submission

From Sema4, Sema4, SCV002535341.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

#	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 Ambry Genetics, SCV004051961.2

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

Description

The c.445_448dupATCT pathogenic mutation, located in coding exon 4 of the SDHD gene, results from a duplication of ATCT at nucleotide positions 445 to 448, causing a translational frameshift with a predicted alternate stop codon (p.C150Yfs*42). This alteration occurs at the 3' terminus of theSDHD gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 31 amino acids. This frameshift impacts the last 10 amino acids of the native protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with SDHD-related disease (Petramala L et al. Eur J Cardiothorac Surg, 2009 Jan;35:189; Piccini V et al. Endocr Relat Cancer, 2012 Apr;19:149-55; Bacca A et al. Head Neck, 2013 Jan;35:23-7; Gasparotto D et al. J Clin Oncol, 2016 Apr;34:e99-e103; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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 7, 2024

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