1-161362384-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBP6

The NM_003001.5(SDHC):c.461T>C(p.Val154Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,262 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V154L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SDHC
NM_003001.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.31

Publications

1 publications found

Variant links:

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

SDHC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a chain Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (size 139) in uniprot entity C560_HUMAN there are 20 pathogenic changes around while only 6 benign (77%) in NM_003001.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07640582).

BP6

Variant 1-161362384-T-C is Benign according to our data. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369. Variant chr1-161362384-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 534369.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHC	NM_003001.5 link	c.461T>C	p.Val154Ala	missense_variant	Exon 6 of 6	ENST00000367975.7	NP_002992.1	Q99643-1A0A0S2Z4B7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHC	ENST00000367975.7 link	c.461T>C	p.Val154Ala	missense_variant	Exon 6 of 6	1	NM_003001.5	ENSP00000356953.3		Q99643-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151636

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727116

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111824

Other (OTH)

AF:

0.00

AC:

AN:

60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151636

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41218

American (AMR)

AF:

0.00

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67944

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Gastrointestinal stromal tumor;C1854336:Pheochromocytoma/paraganglioma syndrome 3

Uncertain:1

Mar 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 154 of the SDHC protein (p.Val154Ala). This variant is present in population databases (no rsID available, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with SDHC-related conditions. ClinVar contains an entry for this variant (Variation ID: 534369). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Benign:1

Jan 12, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Benign

-0.30

CADD

Benign

0.58

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.16

T;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0054

LIST_S2

Benign

0.45

T;T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.076

T;T;T

MetaSVM

Benign

-0.76

PhyloP100

-1.3

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.3

N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.52

T;T;T

Sift4G

Benign

0.61

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.029

MutPred

0.53

Loss of sheet (P = 0.0054);.;.;

MVP

0.61

MPC

2.2

ClinPred

0.024

GERP RS

-11

Varity_R

0.025

gMVP

0.36

Mutation Taster

=87/13

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over