11-112088906-G-T

Position:

• chr11-112088906-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_003002.4(SDHD):​c.209G>T​(p.Arg70Met) 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. 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. R70T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.54

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 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 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 chr11-112088906-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 820714.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 11-112088906-G-T is Pathogenic according to our data. Variant chr11-112088906-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 486436.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-112088906-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.209G>T	p.Arg70Met	missense_variant	3/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.209G>T	p.Arg70Met	missense_variant	3/4	1	NM_003002.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2017

The p.R70M variant (also known as c.209G>T), located in coding exon 3 of the SDHD gene, results from a G to T substitution at nucleotide position 209. The arginine at codon 70 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in the literature in multiple individuals diagnosed with paragangliomas (Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27; Haller F et al. Endocr. Relat. Cancer, 2014 Aug;21:567-77; Persu A et al. J. Hypertens., 2008 Jul;26:1395-401; van Nederveen FH et al. Lancet Oncol., 2009 Aug;10:764-71). This amino acid position is well 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	0.90
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;D;.;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;H;.;.;H;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.8	D;.;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.95
MutPred		0.99		Gain of catalytic residue at V72 (P = 0.1426);Gain of catalytic residue at V72 (P = 0.1426);Gain of catalytic residue at V72 (P = 0.1426);Gain of catalytic residue at V72 (P = 0.1426);Gain of catalytic residue at V72 (P = 0.1426);.;
MVP		0.98
MPC		0.79
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.89
gMVP		0.94

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: rs755047928; hg19: chr11-111959630;