rs778582853

Variant names:

• chr1-161340629-G-A
• rs778582853
• NM_003001.5:c.215G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-161340629-G-A
• chr1-161340629-G-T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_003001.5(SDHC):​c.215G>A​(p.Arg72His) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002728464: Based on internal structural analysis, p.R72H disrupts the catalytic function of succinate dehydrogenase through impacts on quinone binding and/or reduction to quinol (Sun F et al. Cell, 2005 Jul" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R72G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SDHC NM_003001.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.31
• Publications: 5 publications found

Genes affected

SDHC (HGNC:10682): (succinate dehydrogenase complex subunit C) This gene encodes one of four nuclear-encoded subunits that comprise succinate dehydrogenase, also known as mitochondrial complex II, a key enzyme complex of the tricarboxylic acid cycle and aerobic respiratory chains of mitochondria. The encoded protein is one of two integral membrane proteins that anchor other subunits of the complex, which form the catalytic core, to the inner mitochondrial membrane. There are several related pseudogenes for this gene on different chromosomes. Mutations in this gene have been associated with paragangliomas. Alternatively spliced transcript variants have been described. [provided by RefSeq, May 2013]

SDHC Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma/paraganglioma syndrome 3

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

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002728464: Based on internal structural analysis, p.R72H disrupts the catalytic function of succinate dehydrogenase through impacts on quinone binding and/or reduction to quinol (Sun F et al. Cell, 2005 Jul;121:1043-57; Lemarie A et al. Mitochondrion, 2009 Jul;9:254-60; Kluckova K et al. Cell Death Dis, 2015 May;6:e1749).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 29 uncertain in NM_003001.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-161340628-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1786711.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 1-161340629-G-A is Pathogenic according to our data. Variant chr1-161340629-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 407044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003001.5. 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
	SDHC	NM_003001.5	MANE Select	c.215G>A	p.Arg72His	missense	Exon 4 of 6	NP_002992.1	Q99643-1
	SDHC	NM_001407115.1		c.335G>A	p.Arg112His	missense	Exon 5 of 7	NP_001394044.1
	SDHC	NM_001035511.3		c.215G>A	p.Arg72His	missense	Exon 4 of 5	NP_001030588.1	Q99643-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHC	ENST00000367975.7	TSL:1 MANE Select	c.215G>A	p.Arg72His	missense	Exon 4 of 6	ENSP00000356953.3	Q99643-1
	SDHC	ENST00000342751.8	TSL:1	c.215G>A	p.Arg72His	missense	Exon 4 of 5	ENSP00000356952.3	Q99643-2
	SDHC	ENST00000432287.6	TSL:1	c.113G>A	p.Arg38His	missense	Exon 3 of 5	ENSP00000390558.2	Q99643-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 248980 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461644 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727134

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111826

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Gastrointestinal stromal tumor (1)
1	-	-	Gastrointestinal stromal tumor;C1854336:Pheochromocytoma/paraganglioma syndrome 3 (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hereditary pheochromocytoma and paraganglioma (1)
1	-	-	not provided (1)
1	-	-	Pheochromocytoma/paraganglioma syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		4.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.88		Loss of methylation at R72 (P = 0.0149)
MVP		0.99
MPC		0.72
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.80
gMVP		0.94
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs778582853; hg19: chr1-161310419;