1-161314406-A-G

Position:

chr1-161314406-A-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PS1_ModeratePP3PP5_Very_Strong

The NM_003001.5(SDHC):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000372 in 1,613,650 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SDHC
NM_003001.5 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.48

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_003001.5 (SDHC) was described as [Pathogenic] in Lovd

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 1-161314406-A-G is Pathogenic according to our data. Variant chr1-161314406-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 407060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161314406-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHC	NM_003001.5 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/6	ENST00000367975.7	NP_002992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHC	ENST00000367975.7 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/6	1	NM_003001.5	ENSP00000356953	P1	Q99643-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251262

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS 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:

0.00000274

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151782

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74114

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Paragangliomas 3

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 15, 2024	This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30201732, 30877234, 16249420, 11062460, 25720320]. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 12, 2018	This rare c.1A>G (p.Met1?) variant (seen once in gnomAD) in the SDHC gene is predicted to result in a start codon loss of the major biological transcripts. The variant has been observed in multiple unrelated individuals paraganglioma/pheochromocytoma (PMID 16249420, 19351833, 19454582). Predicted start codon loss with different nucleotide changes in this gene has been also observed in other individuals with paraganglioma (PMID : 19351833) . Therefore, this c.1A>G (p.Met1?) variant variant is considered as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 17, 2020	The variant c.1A>G affects the initiator methionine of the SDHC mRNA. This variant is present in population databases (gnomAD v30.001%) and has been reported in the literature in 3 individuals affected with paraganglioma/pheochromocytoma and gastrointestinal stromal tumors [PMID: 23282968; PMID: 22517554; PMID: 19454582], and in a family with Paraganglioma Syndrome [PMID: 16249420]. Two different variants (c.2T>A and c.3G>A) that disrupt the same methionine initiator have been reported in patients and families affected with head and neck paragangliomas [PMID: 19351833], paragangliomas [PMID: 11062460], and renal cell carcinoma [PMID: 22351710], indicating that this methionine initiator of SDHC may be critical for protein function. Based on the available evidence, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Gastrointestinal stromal tumor;C1854336:Paragangliomas 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

This sequence change affects the initiator methionine of the SDHC mRNA. The next in-frame methionine is located at codon 38. This variant is present in population databases (rs755235380, gnomAD 0.006%). Disruption of the initiator codon has been observed in individuals with clinical features of SDHC-related conditions (PMID: 11062460, 16249420, 19454582, 22351710, 22517554, 23282968). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 407060). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 28, 2023

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19454582, 22517557, 27011036, 23282968, 19351833, 28748451, 16249420, 31589614, 33087929, 34558728, 24096523, 31447099, 22517554, 22351710, 11062460, 34750850, 30201732, 30877234) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 21, 2022

The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the SDHC gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. This mutation has previously been reported in multiple individuals diagnosed with paragangliomas (Schiavi F et al. JAMA. 2005 Oct;294:2057-63; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Neumann HP et al. Cancer Res. 2009 Apr;69:3650-6; Am J Surg Pathol 2013 Feb;37(2):234-40; Niemann S et al. Nat Genet 2000 Nov;26(3):268-70). The mutation was also detected in an individual whose GIST tumor showed a loss of SDHB expression and intact SDHA expression on IHC (Miettinen M et al. Am. J. Surg. Pathol. 2013 Feb;37:234-40). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. 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

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.66

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;.;.;.;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.90

D;D;D;D;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

1.0

D;D;D;D;D

PROVEAN

Benign

-1.1

N;N;N;N;D

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Uncertain

0.026

D;D;D;D;D

Polyphen

0.043

B;B;B;P;D

Vest4

0.90

MutPred

0.98

Gain of catalytic residue at M1 (P = 0.0212);Gain of catalytic residue at M1 (P = 0.0212);Gain of catalytic residue at M1 (P = 0.0212);Gain of catalytic residue at M1 (P = 0.0212);Gain of catalytic residue at M1 (P = 0.0212);

MVP

0.90

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.53

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.53

Position offset: -1

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