rs1555187574

chr11-112094807-G-Achr11-112094807-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>A(p.Gly106Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G106V) 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:2
• 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 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain 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-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.
• PP5: Variant 11-112094807-G-A is Pathogenic according to our data. Variant chr11-112094807-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1401809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112094807-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-112094807-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.317G>A	p.Gly106Asp	missense_variant, splice_region_variant	4/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.317G>A	p.Gly106Asp	missense_variant, splice_region_variant	4/4	1	NM_003002.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

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

Invitae

Jan 11, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change does not substantially affect SDHD function (PMID: 23175444). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individuals with paragangliomas (PMID: 17041923, 17102085, 19550080, 22241717, 22566194, 29925701). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 106 of the SDHD protein (p.Gly106Asp). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2021

The p.G106D variant (also known as c.317G>A), located in coding exon 4 of the SDHD gene, results from a G to A substitution at nucleotide position 317. The glycine at codon 106 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been identified in numerous individuals with paraganglioma, and was found to segregate with disease in one family (Ogawa K et al. Am. J. Med. Genet. A. 2006 Nov;140:2441-6; Yamashita R et al. Endocr. J. 2009 Jun;56:1129-35; Kimura N et al. Endocr. Pathol. 2010 Jun;21:139-43; Piccini V et al. Endocr. Relat. Cancer. 2012 Apr;19:149-55; Papathomas TG et al. Mod. Pathol. 2015 Jun;28:807-21; Yamanaka M et al. Tohoku J. Exp. Med. 2018 06;245:99-105; Yonamine M et al. Cancers (Basel). 2021 Aug;13). A yeast-based functional assay has shown this alteration resulted in no phenotypic effect on oxidative growth, however, authors hypothesize that yeast may not be a reliable model for SDHD subunit function (Panizza E et al Hum. Mol. Genet. 2013 Feb; 22(4):804-15). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.91
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.24	T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Pathogenic	0.87	D
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.50
Sift	Uncertain	0.0030	D;T
Sift4G	Uncertain	0.029	D;T
Vest4		0.84
MutPred		0.61		Loss of sheet (P = 0.0142);.;
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)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-111965531;