rs104894304

Variant names:

• chr11-112094831-A-G
• rs104894304
• NM_003002.4:c.341A>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_003002.4(SDHD):​c.341A>G​(p.Tyr114Cys) 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 (★★). ClinVar reports functional evidence for this variant: "SCV000205461: Functional studies have shown that the Tyr114Cys variant impacts protein function, and results in complete loss of ubiquinone reductase activity in yeast (Panizza, 2013)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y114H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 8.93
• Publications: 20 publications found

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]

SDHD Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• pheochromocytoma/paraganglioma syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Carney-Stratakis syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• mitochondrial complex 2 deficiency, nuclear type 3

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• mitochondrial complex II deficiency

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intestinal cancer

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000255292 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000205461: Functional studies have shown that the Tyr114Cys variant impacts protein function, and results in complete loss of ubiquinone reductase activity in yeast (Panizza, 2013).; SCV004814332: Functional studies in yeast have shown a complete loss of ubiquinone reductase activity, reduced protein expression, reduced superoxide generation (PMID: 17208193, 23175444, 25328978).; SCV006061527: Functional studies in yeast have shown a complete loss of ubiquinone reductase activity, reduced protein expression, reduced superoxide generation (PMID: 17208193, 23175444, 25328978).; SCV001477811: "In vitro functional analyses in yeast demonstrate a complete loss of ubiquinone reductase activity (Panizza 2013)."; SCV002599968: Published functional studies demonstrate a damaging effect: protein instability, reduced SDH enzyme activity, and increased mtDNA mutability and sensitivity to oxidative stress (Panizza et al., 2013; Chang et al., 2015);; SCV000823357: Experimental studies have shown that this missense change affects SDHD function (PMID: 23175444).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 36 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 chr11-112094830-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 694526.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756
• PP5: Variant 11-112094831-A-G is Pathogenic according to our data. Variant chr11-112094831-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 6900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003002.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHD	NM_003002.4	MANE Select	c.341A>G	p.Tyr114Cys	missense	Exon 4 of 4	NP_002993.1	O14521-1
	SDHD	NM_001276504.2		c.224A>G	p.Tyr75Cys	missense	Exon 3 of 3	NP_001263433.1	O14521-2
	SDHD	NM_001276503.2		c.196A>G	p.Met66Val	missense	Exon 3 of 3	NP_001263432.1	A0A0S2Z4H7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHD	ENST00000375549.8	TSL:1 MANE Select	c.341A>G	p.Tyr114Cys	missense	Exon 4 of 4	ENSP00000364699.3	O14521-1
	SDHD	ENST00000528048.5	TSL:1	c.196A>G	p.Met66Val	missense	Exon 3 of 3	ENSP00000436217.1	O14521-3
	ENSG00000255292	ENST00000532699.1	TSL:3	n.314+5820A>G		intron	N/A	ENSP00000456434.1	H3BRW5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Hereditary pheochromocytoma and paraganglioma (5)
4	-	-	not provided (4)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 (1)
1	-	-	Pheochromocytoma/paraganglioma syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Benign	0.95
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		8.9
PROVEAN	Benign	0.25	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.46	T
Vest4		0.77
MutPred		0.57		Gain of catalytic residue at M112 (P = 0.0013)
MVP		0.97
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.63
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894304; hg19: chr11-111965555;