rs541660851

Variant names:

• chr1-161362359-C-A
• rs541660851
• NM_003001.5:c.436C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-161362359-C-A
• chr1-161362359-C-G
• chr1-161362359-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003001.5(SDHC):​c.436C>A​(p.Pro146Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,610,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. P146S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SDHC NM_003001.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 0.239
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09450275).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHC	NM_003001.5	MANE Select	c.436C>A	p.Pro146Thr	missense	Exon 6 of 6	NP_002992.1
	SDHC	NM_001407115.1		c.556C>A	p.Pro186Thr	missense	Exon 7 of 7	NP_001394044.1
	SDHC	NM_001035511.3		c.272C>A	p.Ser91Tyr	missense	Exon 5 of 5	NP_001030588.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHC	ENST00000367975.7	TSL:1 MANE Select	c.436C>A	p.Pro146Thr	missense	Exon 6 of 6	ENSP00000356953.3
	SDHC	ENST00000342751.8	TSL:1	c.272C>A	p.Ser91Tyr	missense	Exon 5 of 5	ENSP00000356952.3
	SDHC	ENST00000432287.6	TSL:1	c.334C>A	p.Pro112Thr	missense	Exon 5 of 5	ENSP00000390558.2

Frequencies

GnomAD3 genomes AF: 0.00000671 AC: 1 AN: 149030 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461386 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 726996

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111694

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome AF: 0.00000671 AC: 1 AN: 149030 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 72420

African (AFR) AF: 0.00 AC: 0 AN: 40248

American (AMR) AF: 0.00 AC: 0 AN: 14910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5076

South Asian (SAS) AF: 0.00 AC: 0 AN: 4726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9848

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67494

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Gastrointestinal stromal tumor (1)
-	1	-	Gastrointestinal stromal tumor;C1847319:Carney-Stratakis syndrome;C1854336:Pheochromocytoma/paraganglioma syndrome 3 (1)
-	1	-	Gastrointestinal stromal tumor;C1854336:Pheochromocytoma/paraganglioma syndrome 3 (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)
-	1	-	Pheochromocytoma/paraganglioma syndrome 3 (1)
-	1	-	SDHC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-0.33	T
PhyloP100		0.24
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.21
Sift	Benign	0.25	T
Sift4G	Benign	0.30	T
Polyphen		0.014	B
Vest4		0.12
MutPred		0.44		Gain of MoRF binding (P = 0.0715)
MVP		0.88
MPC		2.1
ClinPred		0.48	T
GERP RS		-0.36
Varity_R		0.16
gMVP		0.46
Mutation Taster		=75/25	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: rs541660851; hg19: chr1-161332149;