rs34677591

chr11-112086941-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003002.4(SDHD):c.34G>A(p.Gly12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0084 in 1,614,148 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0070 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (68 hom.)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:25 O:1
• Conservation: PhyloP100: -0.230

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056276977).
• BP6: Variant 11-112086941-G-A is Benign according to our data. Variant chr11-112086941-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6895.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Benign=18, Likely_benign=3, Uncertain_significance=1}. Variant chr11-112086941-G-A is described in Lovd as [Benign]. Variant chr11-112086941-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00705 (1073/152298) while in subpopulation AMR AF= 0.0116 (177/15300). AF 95% confidence interval is 0.0102. There are 5 homozygotes in gnomad4. There are 487 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.34G>A	p.Gly12Ser	missense_variant	1/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.34G>A	p.Gly12Ser	missense_variant	1/4	1	NM_003002.4	P1

Frequencies

GnomAD3 genomes AF: 0.00705 AC: 1073 AN: 152180 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00992

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00749 AC: 1882 AN: 251370 Hom.: 13 AF XY: 0.00754 AC XY: 1025 AN XY: 135852

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00911

Gnomad ASJ exome AF: 0.00972

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00291

Gnomad FIN exome AF: 0.00439

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00854 AC: 12482 AN: 1461850 Hom.: 68 Cov.: 32 AF XY: 0.00842 AC XY: 6125 AN XY: 727230

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00991

Gnomad4 ASJ exome AF: 0.00987

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00290

Gnomad4 FIN exome AF: 0.00427

Gnomad4 NFE exome AF: 0.00954

Gnomad4 OTH exome AF: 0.00866

GnomAD4 genome AF: 0.00705 AC: 1073 AN: 152298 Hom.: 5 Cov.: 32 AF XY: 0.00654 AC XY: 487 AN XY: 74468

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00480

Gnomad4 NFE AF: 0.00992

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00983 Hom.: 13

Bravo AF: 0.00804

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0112 AC: 96

ExAC AF: 0.00726 AC: 881

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0124

EpiControl AF: 0.0114

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:25 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:9 Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Gly12Ser variant in SDHD has been reported in at least 18 individuals with Cowden or Cowden-like Syndrome (PMID: 21979946, 18678321), 8 individuals with pheochromocytoma or paraganglioma (PMID: 11156372, 11526495, 12111639, 12386824, 15032977, 23666964), in tumors from 2 individuals (PMID: 12007193), in other cohorts with other phenotypes (PMID: 24728327, 22703879), and has been identified in 1.019% (1316/129110) of European (non-Finnish) chromosomes, including 8 homozygotes, 1.013% (105/10370) of Ashkenazi Jewish chromosomes, including 1 homozygote, and 0.9173% (325/5430) of Latino chromosomes, including 3 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs34677591). This variant has also been reported in ClinVar as a VUS, likely benign, and benign variant (Variation ID: 6895). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population and pathogenic variants in this gene have incomplete penetrance (PMID: 29386252). In vitro functional studies provide some evidence that the p.Gly12Ser variant may impact growth pathways and apoptosis (PMID: 18678321, 21979946, 25149476). However, these types of assays may not accurately represent biological function and a yeast model did not match a cancer-related phenotype (PMID: 23175444). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The Glycine (Gly) at position 12 is not highly conserved in mammals and evolutionary distant species, and 5 species (Chinese tree shrew, prairie vole, chinese hamster, mouse, rat) carry a Serine (Ser), supporting that this change at this position may be tolerated. One additional variant, resulting in a different amino acid change at the same position, p.Gly12Asp, has been reported as a VUS in association with disease in ClinVar (Variation ID: 465235). In summary, the clinical significance of the p.Gly12Ser variant is uncertain. ACMG/AMP Criteria applied: BS1, PS4, PS3_Moderate (Richards 2015). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 23, 2014	Gly12Ser in exon 1 of SDHD: This variant has been identified in 1% (36/3612) of patient chromosomes with varying cancer types that included pheochromocytoma, p araganglioma, Cowden and Cowden-like syndromes, and athersclerosis (Gimm 2000, L eube 2004, Ni 2008, Ni 2012, Johnston 2012, Lendavi 2012, Rattenbery 2013). Howe ver, this variant has also been identified in 1.1% (96/8594) European American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu) and 2.5% (6/330) of Puerto Rican and Colombian chromosomes from the 1000 Genomes Project (dbSNP rs34677591). Furthermore, glycine (Gly) at position 12 is not c onserved in mammals or evolutionarily distant species and 5 mammals (tree shrew, vole, hamster, mouse, and rat) carry a serine (Ser) at this position, supportin g that this change may be tolerated. Two studies have shown that this variant ma y modify cancer risk in individuals with pathogenic variants in familial cancer syndrome genes (Ni 2012, Lindavi 2012), though these findings have not been repl icated. In summary, due to the high and equal allele frequency in patient and co ntrol chromosomes and the lack of conservation, this variant is unlikely to cont ribute to Mendelian disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 28, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 08, 2021	- -

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2016	Variant summary: The SDHD c.34G>A (p.Gly12Ser) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO and MutationTaster not captured due to low reliability index). Functional studies of G12S in the literature have shown mixed results. G12S has been shown to increase ROS levels and activated signaling down the AKT and MAPK pathways, as well as inducing migration and increasing resistance to apoptosis. However, the results of these functional studies may not be a reflection of the in vivo consequence in relation to the PGL/PCC or Cowden Syndrome phenotypes.Population level data suggest that this variant lies in the benign spectrum. Although this variant has been identified in CS, CS-like, and cancer patients, it was also found in 881/121216 control chromosomes (5 homozygotes) at a frequency of 0.007268, which is approximately 4652 times the estimated maximal expected allele frequency of a pathogenic SDHD variant (0.0000016), suggesting this variant is likely a benign polymorphism. Additionally, it was found at an allele frequency of >1% in both the European non-Finnish and other subpopulations of ExAC. Sequence alignment indicates the occurrences in ExAC are unlikely to be from the pseudogenes.Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SDHD: BP4, BS1, BS2 -

Paragangliomas 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 09, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 06, 2015	- -

Pheochromocytoma Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 22, 2015	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 21, 2020	- -

Cowden syndrome 3 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

- -

Mitochondrial complex 2 deficiency, nuclear type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

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	0.091
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	13
Dann	Benign	0.92
DEOGEN2	Benign	0.18	T;.;.;.;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.67	T;T;T;T;T;.;T
MetaRNN	Benign	0.056	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.5	L;L;.;L;.;L;L
MutationTaster	Benign	1.1e-8	A;A;A;A;A
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.21	N;.;N;D;N;N;N
REVEL	Uncertain	0.57
Sift	Benign	0.40	T;.;T;T;T;T;T
Sift4G	Benign	0.77	T;T;T;T;T;T;T
Polyphen		0.0050	B;.;.;.;.;.;.
Vest4		0.14
MVP		1.0
MPC		0.19
ClinPred		0.011	T
GERP RS		-7.3
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.050
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs34677591; hg19: chr11-111957665; COSMIC: COSV54777959; COSMIC: COSV54777959;