11-112094807-G-T

Position:

• chr11-112094807-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_003002.4(SDHD):​c.317G>T​(p.Gly106Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. G106D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHD NM_003002.4 missense, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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]

ENSG00000255292 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a chain Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial (size 102) in uniprot entity DHSD_HUMAN there are 30 pathogenic changes around while only 2 benign (94%) in NM_003002.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-112094807-G-A is described in Lovd as [Likely_pathogenic].
• PP5: Variant 11-112094807-G-T is Pathogenic according to our data. Variant chr11-112094807-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 480806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112094807-G-T is described in Lovd as [Pathogenic]. Variant chr11-112094807-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4	c.317G>T	p.Gly106Val	missense_variant, splice_region_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.317G>T	p.Gly106Val	missense_variant, splice_region_variant	4/4	1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.314+5796G>T		intron_variant		3		ENSP00000456434.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 05, 2022

ClinVar contains an entry for this variant (Variation ID: 480806). This missense change has been observed in individuals with hereditary paraganglioma-pheochromocytoma (PGL-PCC) syndrome (PMID: 19351833; Invitae; external communication). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 106 of the SDHD protein (p.Gly106Val). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly106 amino acid residue in SDHD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17041923, 17102085, 19550080, 22241717, 22566194, 23175444, 29925701). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -

Paragangliomas 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2024

SDHD: PM2, PM5, PS4:Moderate, PP1 -

SDHD-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 15, 2022

The SDHD c.317G>T variant is predicted to result in the amino acid substitution p.Gly106Val. This variant has been reported in multiple individuals with pheochromocytomas and/or paragangliomas (Table S1, Neumann et al. 2009. PubMed ID: 19351833; Table S2, Garrett et al. 2022. PubMed ID: 34906457; Internal Data, PreventionGenetics). It has also been reported to co-segregate with pheochromocytoma-paraganglioma syndrome in two independent multigenerational families (Table 1, Knie et al. 2016. PubMed ID: 26740102; Figure 1, Trache et al. 2022. PubMed ID: 35582561). This variant is not present in a large population database (https://gnomad.broadinstitute.org/), indicating that it is rare. It is interpreted as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/480806/). In addition, a different amino acid substitution at this position (p.Gly106Asp) was previously reported in several individuals with paraganglioma and is interpreted as pathogenic in ClinVar (Ogawa et al. 2006. PubMed ID: 17041923; Yamashita et al. 2009. PubMed ID: 19550080; Panizza et al. 2013. PubMed ID: 23175444; https://www.ncbi.nlm.nih.gov/clinvar/variation/1401809/). The c.317G>T (p.Gly106Val) variant is interpreted as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2020

The p.G106V variant (also known as c.317G>T), located in coding exon 4 of the SDHD gene, results from a G to T substitution at nucleotide position 317. The glycine at codon 106 is replaced by valine, an amino acid with dissimilar properties. This alteration has been reported in multiple probands with head and neck paragangliomas (Neumann HP et al. Cancer Res. 2009 Apr;69(8):3650-6, Ambry internal data). Another alteration at the same position, c.317G>A, has also been reported in numerous individuals with paragangliomas (Ogawa et al. Am J Med Genet.A. 2006. 140(22):2441-2446 and Yamashita et al. Endocr J. 2009. 56(9):1129-1135, Ambry internal data). 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	0.81
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.21	T;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Pathogenic	0.86	D
PROVEAN	Benign	-0.030	N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0080	D;T
Sift4G	Benign	0.086	T;T
Vest4		0.67
MutPred		0.61		Gain of sheet (P = 0.0827);.;
MVP		0.97
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1555187574; hg19: chr11-111965531;