1-161362413-A-T

Variant names:

• chr1-161362413-A-T
• rs200375156
• NM_003001.5:c.490A>T
• SDHC p.Met164Leu

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003001.5(SDHC):​c.490A>T​(p.Met164Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000324 in 1,612,024 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M164V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00034 (5 hom.)
• Consequence: SDHC NM_003001.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:11
• Conservation: PhyloP100: -0.0940
• Publications: 6 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013089299).
• BP6: Variant 1-161362413-A-T is Benign according to our data. Variant chr1-161362413-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 184146.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000186 (28/150574) while in subpopulation SAS AF = 0.00438 (21/4794). AF 95% confidence interval is 0.00293. There are 1 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 28 AD,Unknown gene.

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.490A>T	p.Met164Leu	missense	Exon 6 of 6	NP_002992.1	Q99643-1
	SDHC	NM_001407115.1		c.610A>T	p.Met204Leu	missense	Exon 7 of 7	NP_001394044.1
	SDHC	NM_001035511.3		c.326A>T	p.Tyr109Phe	missense	Exon 5 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.490A>T	p.Met164Leu	missense	Exon 6 of 6	ENSP00000356953.3	Q99643-1
	SDHC	ENST00000342751.8	TSL:1	c.326A>T	p.Tyr109Phe	missense	Exon 5 of 5	ENSP00000356952.3	Q99643-2
	SDHC	ENST00000432287.6	TSL:1	c.388A>T	p.Met130Leu	missense	Exon 5 of 5	ENSP00000390558.2	Q99643-3

Frequencies

GnomAD3 genomes AF: 0.000186 AC: 28 AN: 150458 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000134

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00438

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000737

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000534 AC: 132 AN: 247162 AF XY: 0.000785

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000190

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000338 AC: 494 AN: 1461450 Hom.: 5 Cov.: 35 AF XY: 0.000479 AC XY: 348 AN XY: 727010

African (AFR) AF: 0.0000299 AC: 1 AN: 33466

American (AMR) AF: 0.000201 AC: 9 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00399 AC: 344 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00348 AC: 20 AN: 5748

European-Non Finnish (NFE) AF: 0.0000756 AC: 84 AN: 1111756

Other (OTH) AF: 0.000596 AC: 36 AN: 60372

GnomAD4 genome AF: 0.000186 AC: 28 AN: 150574 Hom.: 1 Cov.: 31 AF XY: 0.000300 AC XY: 22 AN XY: 73396

African (AFR) AF: 0.00 AC: 0 AN: 40850

American (AMR) AF: 0.000133 AC: 2 AN: 14994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00438 AC: 21 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000737 AC: 5 AN: 67836

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000945

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not specified (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Hereditary pheochromocytoma and paraganglioma (2)
-	-	2	not provided (2)
-	-	1	Gastrointestinal stromal tumor;C1854336:Pheochromocytoma/paraganglioma syndrome 3 (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	Ovarian cancer (1)
-	-	1	Pheochromocytoma/paraganglioma syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.11
DANN	Benign	0.58
DEOGEN2	Benign	0.092	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.040	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.43	T
PhyloP100		-0.094
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.25
Sift	Benign	0.16	T
Sift4G	Benign	0.51	T
Varity_R		0.055
gMVP		0.36
Mutation Taster		=85/15	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs200375156;

hg19: chr1-161332203;