rs786205147

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_003001.5(SDHC):c.224G>A(p.Gly75Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,518 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G75R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SDHC
NM_003001.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.31

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 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 chr1-161340637-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 486434.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 1-161340638-G-A is Pathogenic according to our data. Variant chr1-161340638-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161340638-G-A is described in Lovd as [Pathogenic]. Variant chr1-161340638-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHC	NM_003001.5 link	c.224G>A	p.Gly75Asp	missense_variant	Exon 4 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.224G>A	p.Gly75Asp	missense_variant	Exon 4 of 6	1	NM_003001.5	ENSP00000356953.3		Q99643-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461518

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Carney triad

Pathogenic:1

Section on Endocrinology and Genetics, National Institutes of Health / The Eunice Kennedy Shriver National Institute of Child Health and Human Development

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Gastrointestinal stromal tumor;C1854336:Paragangliomas 3

Pathogenic:1

Oct 25, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individuals with paraganglioma and condroma (PMID: 19351833, 26173966; Invitae). ClinVar contains an entry for this variant (Variation ID: 189841). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHC protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 75 of the SDHC protein (p.Gly75Asp). -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jun 01, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G75D pathogenic mutation (also known as c.224G>A), located in coding exon 4 of the SDHC gene, results from a G to A substitution at nucleotide position 224. The glycine at codon 75 is replaced by aspartic acid, an amino acid with similar properties. In a study of 598 unrelated probands diagnosed with head and neck paraganglioma, this pathogenic variant was detected in 2 individuals (Neumann HP et al. Cancer Res. 2009 Apr;69:3650-6). This pathogenic variant has also been detected in an individual with Carney triad (Boikos SA et al. Eur. J. Hum. Genet. 2016 Apr;24:569-73). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Ambry internal data; Zhou Q et al. Protein Cell. 2011 Jul;2:531-42). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;.;.;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.7

H;H;.;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.4

D;D;D;D;D

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0040

D;D;D;D;D

Sift4G

Uncertain

0.0070

D;D;D;D;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.97

MutPred

0.94

Loss of methylation at R72 (P = 0.0436);Loss of methylation at R72 (P = 0.0436);.;.;.;

MVP

0.98

MPC

1.3

ClinPred

1.0

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.96

gMVP

0.98

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over