11-112087953-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003002.4(SDHD):c.149A>G(p.His50Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00735 in 1,609,602 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H50D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0068 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (48 hom.)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:20 O:1
• Conservation: PhyloP100: 2.52

Genes affected

SDHD (HGNC:10683): (succinate dehydrogenase complex subunit D) This gene encodes a member of complex II of the respiratory chain, which is responsible for the oxidation of succinate. The encoded protein is one of two integral membrane proteins anchoring the complex to the matrix side of the mitochondrial inner membrane. Mutations in this gene are associated with the formation of tumors, including hereditary paraganglioma. Transmission of disease occurs almost exclusively through the paternal allele, suggesting that this locus may be maternally imprinted. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-112087952-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.00989148).
• BP6: Variant 11-112087953-A-G is Benign according to our data. Variant chr11-112087953-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 6909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112087953-A-G is described in Lovd as [Likely_benign]. Variant chr11-112087953-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00679 (1034/152244) while in subpopulation AMR AF= 0.0155 (237/15302). AF 95% confidence interval is 0.0139. There are 6 homozygotes in gnomad4. There are 482 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.149A>G	p.His50Arg	missense_variant	2/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.149A>G	p.His50Arg	missense_variant	2/4	1	NM_003002.4	P1

Frequencies

GnomAD3 genomes AF: 0.00680 AC: 1035 AN: 152126 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00669

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00796

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.00661 AC: 1661 AN: 251460 Hom.: 6 AF XY: 0.00670 AC XY: 911 AN XY: 135910

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00734

Gnomad ASJ exome AF: 0.00833

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00173

Gnomad FIN exome AF: 0.00638

Gnomad NFE exome AF: 0.00913

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.00741 AC: 10795 AN: 1457358 Hom.: 48 Cov.: 29 AF XY: 0.00729 AC XY: 5289 AN XY: 725300

Gnomad4 AFR exome AF: 0.00141

Gnomad4 AMR exome AF: 0.00827

Gnomad4 ASJ exome AF: 0.00877

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00183

Gnomad4 FIN exome AF: 0.00673

Gnomad4 NFE exome AF: 0.00822

Gnomad4 OTH exome AF: 0.00816

GnomAD4 genome AF: 0.00679 AC: 1034 AN: 152244 Hom.: 6 Cov.: 32 AF XY: 0.00647 AC XY: 482 AN XY: 74448

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.00894

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00669

Gnomad4 NFE AF: 0.00796

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.00807 Hom.: 17

Bravo AF: 0.00776

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.00780 AC: 67

ExAC AF: 0.00651 AC: 791

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00981

EpiControl AF: 0.0100

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2 Benign:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:7

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SDHD: PM5, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 04, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 16, 2023	- -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2019	This variant is associated with the following publications: (PMID: 24728327, 23175444, 12386824, 25695889, 29386252, 22703879, 20981092, 14557476, 25694510, 21979946, 18678321, 12696072, 12007193, 25149476, 25376524, 28128698, 27279923, 28164237, 17576205) -

not specified Benign:5 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 09, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 29, 2019	- -

Paragangliomas 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Dec 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 19, 2022	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 29, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Carcinoid tumor of intestine Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Aug 01, 2008

- -

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Pheochromocytoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

SDHD-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Carney-Stratakis syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0027	T
BayesDel_noAF	Pathogenic	0.24
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.;.;.;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;.
MetaRNN	Benign	0.0099	T;T;T;T;T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.9	M;M;.;M;.;M
MutationTaster	Benign	0.99	A;A;A;A;A
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.9	N;.;N;D;N;N
REVEL	Pathogenic	0.68
Sift	Benign	0.065	T;.;D;D;D;T
Sift4G	Benign	0.13	T;T;T;D;T;T
Polyphen		0.98	D;.;.;.;.;.
Vest4		0.53
MVP		0.95
MPC		0.37
ClinPred		0.039	T
GERP RS		4.9
Varity_R		0.18
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11214077; hg19: chr11-111958677;