rs80338846

Positions:

• chr11-112088981-T-C

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.284T>C​(p.Leu95Pro) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L95R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3 O: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 transmembrane_region Helical (size 20) in uniprot entity DHSD_HUMAN there are 15 pathogenic changes around while only 1 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 chr11-112088981-T-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 11-112088981-T-C is Pathogenic according to our data. Variant chr11-112088981-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 21351.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-112088981-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4	c.284T>C	p.Leu95Pro	missense_variant	3/4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.284T>C	p.Leu95Pro	missense_variant	3/4	1	NM_003002.4	ENSP00000364699	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2022

The p.L95P pathogenic mutation (also known as c.284T>C), located in coding exon 3 of the SDHD gene, results from a T to C substitution at nucleotide position 284. The leucine at codon 95 is replaced by proline, an amino acid with similar properties. This alteration has been described as a Dutch founder mutation and has been identified in multiple patients and families with paragangliomas/pheochromocytomas, and was shown to segregate with disease in at least two families (Taschner PE et al. Genes Chromosomes Cancer, 2001 Jul;31:274-81; Cremers CW et al. Otol. Neurotol., 2002 Sep;23:755-9; Hensen EF et al. Clin. Genet., 2012 Mar;81:284-8; van Hulsteijn LT et al. Clin. Endocrinol. (Oxf), 2013 Dec;79:824-31; Bayley JP et al. BMC Med. Genet., 2014 Oct;15:111; Heesterman BL et al. Eur J Hum Genet, 2018 09;26:1339-1347; Richter S et al. Genet Med, 2019 03;21:705-717; Dreijerink KMA et al. J Clin Endocrinol Metab, 2019 11;104:5421-5426). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary pheochromocytoma-paraganglioma Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;D;.;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H;.;.;H;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.4	D;.;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.019	D;.;D;D;D;D
Sift4G	Uncertain	0.023	D;D;D;D;D;D
Polyphen		0.73	P;.;.;.;.;.
Vest4		0.99
MutPred		0.97		Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);.;
MVP		0.98
MPC		0.96
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.98
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: rs80338846; hg19: chr11-111959705;