rs786202403

chr11-112089001-C-Achr11-112089001-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>A(p.His102Asn) 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, 0.993
• PP5: Variant 11-112089001-C-A is Pathogenic according to our data. Variant chr11-112089001-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.304C>A	p.His102Asn	missense_variant	3/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.304C>A	p.His102Asn	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

Feb 09, 2019

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 observed in individuals with SDHD-related conditions (PMID: 10657297, 12811540, 19454582, 22025150, 22241717), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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 several individuals with pheochromocytoma and/or paraganglioma (Invitae, external communication). ClinVar contains an entry for this variant (Variation ID: 185719). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with asparagine at codon 102 of the SDHD protein (p.His102Asn). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and asparagine. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 2014

The p.H102N variant (also known as c.304C>A), located in coding exon 3 of theSDHD gene, results from a C to A substitution at nucleotide position 304. The histidine at codon 102 is replaced by asparagine, an amino acid with similar properties. This alteration has been observed in at least one individual who has a personal or family history that is consistent with SDHD-associated disease (Ambry internal data). Several other alterations at the same codon have been described in individuals with head and neck paraganglioma: p.H102L, p.H102R, p.H102Y, and p.H102P (Poeppel TD, J. Clin. Oncol. 2011 Nov; 29(33):e812-5. Piccini V, Endocr. Relat. Cancer 2012 Apr; 19(2):149-55. Baysal BE, Science 2000 Feb; 287(5454):848-51. Burnichon N, J. Clin. Endocrinol. Metab. 2009 Aug; 94(8):2817-27). Based on internal structural assessment, this alteration disrupts the residue required to bind the heme cofactor in SDHD (Sun F et al. Cell, 2005 Jul;121:1043-57). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. 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	0.90
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;T;T;.;D
M_CAP	Pathogenic	0.48	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	-6.9	D;.;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0080	D;.;D;D;D;D
Sift4G	Uncertain	0.037	D;D;D;T;D;T
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.97
MutPred		0.98		Loss of catalytic residue at L101 (P = 0.188);Loss of catalytic residue at L101 (P = 0.188);Loss of catalytic residue at L101 (P = 0.188);Loss of catalytic residue at L101 (P = 0.188);Loss of catalytic residue at L101 (P = 0.188);.;
MVP		0.94
MPC		0.78
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.93
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.29		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;