chr11-112086941-G-A

Position:

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

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]

SDHD links:

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4 linkuse as main transcript	c.34G>A	p.Gly12Ser	missense_variant	1/4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8 linkuse as main transcript	c.34G>A	p.Gly12Ser	missense_variant	1/4	1	NM_003002.4	ENSP00000364699	P1	O14521-1

Frequencies

GnomAD3 genomes

AF:

0.00705

AC:

1073

AN:

152180

Hom.:

Cov.:

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.:

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.:

Cov.:

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.:

Cov.:

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.:

Bravo

AF:

0.00804

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0112

AC:

ExAC

AF:

0.00726

AC:

881

Asia WGS

AF:

0.00289

AC:

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

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	-	- -
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, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
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	Genetic Services Laboratory, University of Chicago	Nov 08, 2021	- -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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	- -

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SDHD: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Paragangliomas 1

Benign:3

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	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 09, 2022	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

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

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.18

T;.;.;.;.;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.12

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

MutationAssessor

Benign

1.5

L;L;.;L;.;L;L

MutationTaster

Benign

1.1e-8

A;A;A;A;A

PrimateAI

Benign

0.39

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over