NM_003002.3(SDHD):c.149A>G (p.His50Arg) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting classifications of pathogenicity (4 submissions)
Last evaluated:: Oct 4, 2017
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:: RCV000034696.1

Allele description

NM_003002.3(SDHD):c.149A>G (p.His50Arg)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

11q23.1

Genomic location:

Preferred name:

NM_003002.3(SDHD):c.149A>G (p.His50Arg)

Other names:

SDHD, HIS50ARG (rs11214077)

HGVS:

NC_000011.10:g.112087953A>G
NG_012337.3:g.6107A>G
NM_001276504.1:c.53-914A>G
NM_001276506.1:c.149A>G
NM_003002.3:c.149A>G
NP_001263435.1:p.His50Arg
NP_002993.1:p.His50Arg
NC_000011.9:g.111958677A>G
NG_012337.2:g.6107A>G
NM_003002.2:c.149A>G
NR_077060.1:n.233A>G
O14521:p.His50Arg
p.H50R

Protein change:

H50R; HIS50ARG

Links:

UniProtKB: O14521#VAR_017871; OMIM: 602690.0019; dbSNP: rs11214077

GMAF:

0.0066(G), 11214077

NCBI 1000 Genomes Browser:

rs11214077

Allele Frequency:

0.0063, GO-ESP

Molecular consequence:

NM_001276504.1:c.53-914A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_003002.3:c.149A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_077060.1:n.233A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Identifiers:: MedGen: CN517202

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000043498	Biesecker Lab/Human Development Section,National Institutes of Health - ClinSeq	no assertion criteria provided	variant of unknown significance (Jul 13, 2012)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000574910	Praxis fuer Humangenetik Tuebingen	no assertion criteria provided (PHGTv1.pdf)	Uncertain significance (Jan 31, 2017)	germline	clinical testing
SCV000609650	Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Oct 4, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000698139	Integrated Genetics/Laboratory Corporation of America	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Aug 31, 2016)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 18678321, 25149476, 25695889, 23175444, 25694510, 12696072, 15623805, 22703879 LabCorp Variant Classification Summary - May 2015.docx Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	4	not provided	not provided	572	not provided	research
not provided	germline	not provided	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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes.

Ni Y, Zbuk KM, Sadler T, Patocs A, Lobo G, Edelman E, Platzer P, Orloff MS, Waite KA, Eng C.

Am J Hum Genet. 2008 Aug;83(2):261-8. doi: 10.1016/j.ajhg.2008.07.011.

PubMed [citation]

PMID:: 18678321
PMCID:: PMC2495063

See all PubMed Citations (9)

Details of each submission

From Biesecker Lab/Human Development Section,National Institutes of Health - ClinSeq, SCV000043498.1

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

Description

The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See PubMed ID:22703879 for details.

Description

Converted during submission to Uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	572	not provided	discovery		4	not provided	not provided	not provided

From Praxis fuer Humangenetik Tuebingen, SCV000574910.3

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

#	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		1	not provided	not provided	not provided

From Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics, SCV000609650.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	0.008407	not provided	not provided

From Integrated Genetics/Laboratory Corporation of America, SCV000698139.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Variant summary: The SDHD c.149A>G (p.His50Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). In vitro studies provided conflicting results in affecting cell growth, PTEN function, P-Akt and P-MAPK levels. This variant has been reported in numerous patients with various cancer phenotypes or atherosclerosis phenotypes without co-segregation evidence. This variant was found in 827/123658 control chromosomes (6 homozygotes) at a frequency of 0.0066878, which is approximately 4280 times the estimated maximal expected allele frequency of a pathogenic SDHD variant (0.0000016), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. In summary, this variant is unlikely to be pathogenic in Mendelian inheritance, however, the possibility of it being a disease modifier can not be ruled out. Therefore, this variant is classified as likely benign.

#	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 26, 2018

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