11-112094969-G-T

Position:

chr11-112094969-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM4PP5

The NM_003002.4(SDHD):c.479G>T(p.Ter160LeuextTer3) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000931 in 1,610,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. *160*) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

SDHD
NM_003002.4 stop_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:5

Conservation

PhyloP100: 1.54

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 Uncertain_significance. Variant got 3 ACMG points.

PM4

Stoplost variant in NM_003002.4 Downstream stopcodon found after 170 codons.

PP5

Variant 11-112094969-G-T is Pathogenic according to our data. Variant chr11-112094969-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 156154.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4 linkuse as main transcript	c.479G>T	p.Ter160LeuextTer3	stop_lost	4/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8 linkuse as main transcript	c.479G>T	p.Ter160LeuextTer3	stop_lost	4/4	1	NM_003002.4	P1	O14521-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247668

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134696

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:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000823

AC:

AN:

1458320

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

725576

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:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2023	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); Normal stop codon changed to a Leucine codon, leading to the addition of 3 amino acids at the C-terminus; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.X104LextX3; This variant is associated with the following publications: (PMID: 24367056, 34012134, 33162331) -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 20, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Extension variant reported in 1 proband with autosomal recessive encephalomyopathy and MT complex II deficiency - proband carried E69K on other allele. Complementation of a patient cell line supported the pathogenicity of the SDHD variants. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2018	Variant summary: SDHD c.479G>T (p.X160LeuextX3) changes the termination codon and is predicted to lead to an extended protein with additional 3 amino acids added to the normal C-terminus. The variant allele was found at a frequency of 4.1e-06 in 242834 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.479G>T has been reported in the literature in one individual affected with mitochondrial complex II deficiency in compound heterozygous state (Jackson_2014). This report does not provide unequivocal conclusions about association of the variant with Hereditary Paraganglioma-Pheochromocytoma Syndrome. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about causality of the variant (Jackson_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary pheochromocytoma-paraganglioma

Uncertain:2

Uncertain significance, no assertion criteria provided	research	Section on Medical Neuroendocrinolgy, National Institutes of Health	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This variant is a termination codon variant that changes the translational stop signal of the SDHD gene to leucine and extends the length of the SDHD protein by 3 additional amino acids. A functional complementation experiment using patient fibroblasts harboring the SDHD c.205G>A p.(Glu69Lys) and SDHD c.479G>T p.160Leuext3 variants demonstrated that transduction with either mutant transcript was unable to rescue the reduced expression and activity of the succinate dehydrogenase complex, whereas transduction of the patient fibroblasts with the wild type SDHD cDNA transcript restored SDH activity. Mitochondrial complex II activity and levels were also significantly reduced in patient cells (PMID: 24367056). This variant has been reported in trans with another SDHD variant (c.205G>A, p.Glu69Lys) in a single individual with autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency (PMID: 24367056). The parents were heterozygous for one of the variants each and have been referred for tumor surveillance. Screening with 24 h measurements of blood pressure and urinary catecholamines of both parents was normal. The SDHD / c.479G>T / p.160Leuext3 variant has been observed in two individuals with paraganglioma at NIH (ClinVar, SCV000599548.1, personal communication). A similar stop loss variant in the SDHD gene, (c.479_480insGT, p.160Trpext8) has been identified in a patient with bilateral carotid paragangliomas (PMID: 31508186). The SDHD c.479G>T p.160Leuext3 variant has been identified in 1/247668 chromosomes in the general population by the Genome Aggregation Database (gnomAD). While the evidence may support a causal role in autosomal recessive mitochondrial complex II deficiency, the clinical significance with respect to autosomal dominant paraganglioma-pheochromocytoma syndrome is uncertain. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Mitochondrial complex 2 deficiency, nuclear type 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2014

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.479G>T variant (also known as p.*160Lext*3), located in coding exon 4 of the SDHD gene, results from a G to T substitution at nucleotide position 479, which is the second to last nucleotide of the SDHD gene. This alteration disrupts the stop codon of the SDHD gene and is predicted to preserve the native sequence while resulting in the elongation of the protein by 3 amino acids. The exact functional effect of the additional amino acids is unknown. This alteration has been reported as compound heterozygous with a second SDHD alteration, p.E69K, 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). Functional studies demonstrated that the introduction of this variant to patient cells was unable to recover complex II formation compared to a WT control (Jackson CB et al. J. Med. Genet., 2014 Mar;51:170-5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic in association with autosomal recessive mitochondrial complex II deficiency when present along with a second pathogenic or likely pathogenic variant on the other allele; however, the clinical significance in regards to paraganglioma-pheochromocytoma syndrome is unlikely. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

This sequence change disrupts the translational stop signal of the SDHD mRNA. It is expected to extend the length of the SDHD protein by 3 additional amino acid residues. This variant is present in population databases (rs201372601, gnomAD 0.0009%). This protein extension has been observed in individual(s) with mitochondrial complex II deficiency (PMID: 24367056). ClinVar contains an entry for this variant (Variation ID: 156154). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this protein extension affects SDHD function (PMID: 24367056). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

0.0056

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.86

Eigen

Pathogenic

0.83

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

D;D;D;N;N

Vest4

0.27

GERP RS

3.9

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