11-112089001-C-T

Position:

• chr11-112089001-C-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.304C>T​(p.His102Tyr) 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. H102L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.44

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 hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 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 chr11-112089002-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 11-112089001-C-T is Pathogenic according to our data. Variant chr11-112089001-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 846101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112089001-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.304C>T	p.His102Tyr	missense_variant	3/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.304C>T	p.His102Tyr	missense_variant	3/4	1	NM_003002.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 25, 2019

This sequence change replaces histidine with tyrosine at codon 102 of the SDHD protein (p.His102Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: 10657297, 12811540, 19454582, 22025150, 22241717). 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 (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 has been observed in individual(s) with paraganglioma-pheochromocytoma syndrome (PMID: 22241717, Invitae). This variant is not present in population databases (ExAC no frequency). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2020

The p.H102Y pathogenic mutation (also known as c.304C>T), located in coding exon 3 of the SDHD gene, results from a C to T substitution at nucleotide position 304. The histidine at codon 102 is replaced by tyrosine, an amino acid with few similar properties. This variant has been reported in multiple individuals with a clinical diagnossis of paraganglioma-pheochromocytoma (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). Several other variants at the same codon (p.H102L, p.H102R, p.H102Y, and p.H102P) have been described in individuals with head and neck paraganglioma (Poeppel TD et al J. Clin. Oncol. 2011 Nov;29(33):e812-5; Piccini V et al. Endocr. Relat. Cancer. 2012 Apr;19(2):149-55; Baysal BE et al. Science. 2000 Feb;287(5454):848-51; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94(8):2817-27). Based on internal structural analysis, this variant is anticipated to disrupt a region of known function (Ambry internal data; Sun F et al. Cell. 2005 Jul;121(7):1043-57; Zhou Q et al. Protein Cell. 2011 Jul;2(7):531-42). 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	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T;T;T;.;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.9	H;H;.;.;H;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.0	D;.;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;.;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.98
MutPred		0.98		Loss of catalytic residue at L101 (P = 0.1775);Loss of catalytic residue at L101 (P = 0.1775);Loss of catalytic residue at L101 (P = 0.1775);Loss of catalytic residue at L101 (P = 0.1775);Loss of catalytic residue at L101 (P = 0.1775);.;
MVP		0.98
MPC		0.70
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.84
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: 10

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

Publications

LitVar

Other links and lift over

dbSNP: rs786202403; hg19: chr11-111959725;