chr11-112094902-G-A

Position:

• chr11-112094902-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000375549.8(SDHD):​c.412G>A​(p.Gly138Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G138E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SDHD ENST00000375549.8 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.58

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 Pathogenic. Variant got 18 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 ENST00000375549.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-112094903-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1479490.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 11-112094902-G-A is Pathogenic according to our data. Variant chr11-112094902-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 187700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4	c.412G>A	p.Gly138Arg	missense_variant	4/4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.412G>A	p.Gly138Arg	missense_variant	4/4	1	NM_003002.4	ENSP00000364699	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 09, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 138 of the SDHD protein (p.Gly138Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paraganglioma-pheochromocytoma syndrome (PMID: 29875428, 31492822; Invitae). ClinVar contains an entry for this variant (Variation ID: 187700). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 31, 2016

This variant is denoted SDHD c.412G>A at the cDNA level, p.Gly138Arg (G138R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. SDHD Gly138Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. SDHD Gly138Arg occurs at a position that is conserved across species and is located in the helical transmembrane region (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider SDHD Gly138Arg to be a likely pathogenic variant. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2023

The p.G138R variant (also known as c.412G>A), located in coding exon 4 of the SDHD gene, results from a G to A substitution at nucleotide position 412. The glycine at codon 138 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been observed in individuals with a personal and/or family history that is consistent with SDHD-related disease (Ambry internal data; Yonamine M et al. Cancers (Basel) 2021 Aug;13(16); Turner SA et al. Genet Med 2019 Feb;21(2):426-430). Based on internal structure analysis, this alteration is predicted to destabilize the SDHD-SDHC protein-protein interface (Sun F et al. Cell. 2005 Jul; 121(7):1043-57). 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 likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.93		Gain of methylation at G138 (P = 0.0487);.;
MVP		0.99
MPC		0.82
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.99

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

Other links and lift over

dbSNP: rs786203932; hg19: chr11-111965626;