chr11-112088902-G-A

Position:

chr11-112088902-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_003002.4(SDHD):c.205G>A(p.Glu69Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SDHD
NM_003002.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 9.35

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:

ENSG00000255292 (HGNC:):

ENSG00000255292 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a transmembrane_region Helical (size 21) in uniprot entity DHSD_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_003002.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 11-112088902-G-A is Pathogenic according to our data. Variant chr11-112088902-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 156153.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4 linkuse as main transcript	c.205G>A	p.Glu69Lys	missense_variant	3/4	ENST00000375549.8	NP_002993.1	O14521-1A0A0S2Z4J3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8 linkuse as main transcript	c.205G>A	p.Glu69Lys	missense_variant	3/4	1	NM_003002.4	ENSP00000364699.3		O14521-1
ENSG00000255292	ENST00000532699.1 linkuse as main transcript	n.205G>A		non_coding_transcript_exon_variant	3/6	3		ENSP00000456434.1		H3BRW5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251256

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460472

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726538

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mitochondrial complex II deficiency, nuclear type 1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Rare Disease Group, University of Exeter

Jul 23, 2020

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 69 of the SDHD protein (p.Glu69Lys). This variant is present in population databases (rs202198133, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of autosomal recessive mitochondrial complex II deficiency (PMID: 24367056, 34012134). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 156153). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHD protein function. Experimental studies have shown that this missense change affects SDHD function (PMID: 24367056). For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial complex 2 deficiency, nuclear type 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2014

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: reduced enzyme activities of the individual respiratory chains complexes in skeletal muscle and inability to restore the complex II assembly in a fibroblast cell line (Jackson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29504908, 33162331, 34012134, 24367056) -

SDHD-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2024

The SDHD c.205G>A variant is predicted to result in the amino acid substitution p.Glu69Lys. This variant has been reported as compound heterozygous state with a pathogenic variant in SDHD in an individual with autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency (Jackson et al 2014. PubMed ID: 24367056). In the same publication, this variant showed no effect on SDHD restoration comparing to wild type by functional complementation of patient’s fibroblasts. In addition, this variant has been reported as homozygous in several members of one family with mitochondrial complex II deficiency (Lin et al 2021. PubMed ID: 34012134). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/156153/). This variant is interpreted as likely pathogenic. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2024

The p.E69K variant (also known as c.205G>A), located in coding exon 3 of the SDHD gene, results from a G to A substitution at nucleotide position 205. The glutamic acid at codon 69 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in the compound heterozygous state with a second SDHD alteration in an individual with autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency (Jackson CB et al. J Med Genet, 2014 Mar;51:170-5). This alteration was also observed to be homozygous in several members of one family who were determined to have mitochondrial complex II deficiency (Lin S et al. Eur J Hum Genet 2021 10;29(10):1570-1576). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is expected to be causative of autosomal recessive mitochondrial complex II deficiency when present along with a second likely pathogenic/pathogenic variant on the other allele; however, its clinical significance for autosomal dominant paraganglioma-pheochromocytoma syndrome is unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;.;.;.;.;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

D;D;D;D;.;D

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.8

H;H;.;.;H;.

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-4.0

D;.;D;D;D;D

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;.;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

1.0

MutPred

0.95

Gain of MoRF binding (P = 0.0031);Gain of MoRF binding (P = 0.0031);Gain of MoRF binding (P = 0.0031);Gain of MoRF binding (P = 0.0031);Gain of MoRF binding (P = 0.0031);.;

MVP

0.97

MPC

0.78

ClinPred

1.0

GERP RS

5.0

Varity_R

0.98

gMVP

0.96

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

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