rs1060501390

Variant names:

• chr1-161356731-A-G
• rs1060501390
• NM_003001.5:c.296A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-161356731-A-G
• chr1-161356731-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003001.5(SDHC):​c.296A>G​(p.Tyr99Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,812 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y99H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SDHC NM_003001.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.89
• Publications: 2 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: Orphanet, ClinGen
• pheochromocytoma/paraganglioma syndrome 3

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

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927

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.296A>G	p.Tyr99Cys	missense	Exon 5 of 6	NP_002992.1
	SDHC	NM_001407115.1		c.416A>G	p.Tyr139Cys	missense	Exon 6 of 7	NP_001394044.1
	SDHC	NM_001407116.1		c.239A>G	p.Tyr80Cys	missense	Exon 4 of 5	NP_001394045.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHC	ENST00000367975.7	TSL:1 MANE Select	c.296A>G	p.Tyr99Cys	missense	Exon 5 of 6	ENSP00000356953.3
	SDHC	ENST00000432287.6	TSL:1	c.194A>G	p.Tyr65Cys	missense	Exon 4 of 5	ENSP00000390558.2
	SDHC	ENST00000392169.6	TSL:1	c.137A>G	p.Tyr46Cys	missense	Exon 3 of 4	ENSP00000376009.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 249004 AF XY: 0.00000742

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461812 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Gastrointestinal stromal tumor;C1854336:Pheochromocytoma/paraganglioma syndrome 3 (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Hereditary pheochromocytoma-paraganglioma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.9
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		0.94	P
Vest4		0.76
MutPred		0.70		Gain of catalytic residue at L100 (P = 0.0148)
MVP		0.97
MPC		1.2
ClinPred		0.97	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.45
gMVP		0.86
Mutation Taster		=64/36	polymorphism

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: rs1060501390; hg19: chr1-161326521;