chr11-112086941-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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).

Frequency

Genomes: 𝑓 0.0070 ( 5 hom., cov: 32)
Exomes 𝑓: 0.0085 ( 68 hom. )

Consequence

SDHD
NM_003002.4 missense

Scores

3
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:25O:1

Conservation

PhyloP100: -0.230
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Uncertain_significance=1, Benign=18, Likely_benign=3, not_provided=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 GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SDHDNM_003002.4 linkc.34G>A p.Gly12Ser missense_variant Exon 1 of 4 ENST00000375549.8 NP_002993.1 O14521-1A0A0S2Z4J3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SDHDENST00000375549.8 linkc.34G>A p.Gly12Ser missense_variant Exon 1 of 4 1 NM_003002.4 ENSP00000364699.3 O14521-1
ENSG00000255292ENST00000532699.1 linkn.34G>A non_coding_transcript_exon_variant Exon 1 of 6 3 ENSP00000456434.1 H3BRW5

Frequencies

GnomAD3 genomes
AF:
0.00705
AC:
1073
AN:
152180
Hom.:
5
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:2Benign:25Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:9Other:1
Jun 28, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Nov 03, 2017
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Nov 08, 2021
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 22, 2020
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

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). -

Jul 07, 2015
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 23, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:6
Oct 14, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SDHD: BP4, BS1, BS2 -

Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 13, 2012
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: research

- -

May 25, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Paragangliomas 1 Benign:3
Nov 06, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 15, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 09, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Pheochromocytoma Benign:2
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 15, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2
Aug 21, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

May 22, 2015
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Cowden syndrome 3 Uncertain:1
Aug 01, 2008
OMIM
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mitochondrial complex 2 deficiency, nuclear type 3 Benign:1
Jul 15, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Carney-Stratakis syndrome Benign:1
May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34677591; hg19: chr11-111957665; COSMIC: COSV54777959; COSMIC: COSV54777959; API