11-112089002-A-T

Position:

• chr11-112089002-A-T

Variant summary

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

The NM_003002.4(SDHD):​c.305A>T​(p.His102Leu) 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. H102P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.71

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 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 chr11-112089002-A-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 11-112089002-A-T is Pathogenic according to our data. Variant chr11-112089002-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 6898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112089002-A-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.305A>T	p.His102Leu	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.305A>T	p.His102Leu	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

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

Jul 01, 2021

This sequence change replaces histidine with leucine at codon 102 of the SDHD protein (p.His102Leu). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with paragangliomas (Invitae). It has also been observed to segregate with disease in related individuals (PMID: 10657297, 12811540). ClinVar contains an entry for this variant (Variation ID: 6898). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.His102 amino acid residue in SDHD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22241717, Invitae, external communication). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Paragangliomas 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 04, 2000

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2021

The p.H102L variant (also known as c.305A>T), located in coding exon 3 of the SDHD gene, results from an A to T substitution at nucleotide position 305. The histidine at codon 102 is replaced by leucine, an amino acid with similar properties. This mutation has been reported in multiple individuals with paraganglioma-pheochromocytoma (PGL/PCC) syndrome (Baysal BE et al. Science, 2000 Feb;287:848-51; Astrom K et al. Hum Genet, 2003 Aug;113:228-37; Ambry internal data). Other alterations at the same codon, p.H102N and p.H102Y, have been detected in patients with PGL/PCC syndrome (Piccini V et al. Endocr. Relat. Cancer. 2012 Apr;19(2):149-55; Bacca A et al. Head Neck. 2013 Jan;35(1):23-7; Benn DE et al. Endocr. Relat. Cancer. 2015 Aug;22:T91-103). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T;T;T;T;.;T
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.9	H;H;.;.;H;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-11	D;.;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;.;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.95
MutPred		0.99		Loss of catalytic residue at G103 (P = 0.0541);Loss of catalytic residue at G103 (P = 0.0541);Loss of catalytic residue at G103 (P = 0.0541);Loss of catalytic residue at G103 (P = 0.0541);Loss of catalytic residue at G103 (P = 0.0541);.;
MVP		0.99
MPC		0.82
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.84
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs104894302; hg19: chr11-111959726;