chr11-112086908-A-T

Position:

chr11-112086908-A-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_003002.4(SDHD):c.1A>T(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 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: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SDHD
NM_003002.4 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.35

Variant links:

Genes affected

SDHD (HGNC:10683): (succinate dehydrogenase complex subunit D) This gene encodes a member of complex II of the respiratory chain, which is responsible for the oxidation of succinate. The encoded protein is one of two integral membrane proteins anchoring the complex to the matrix side of the mitochondrial inner membrane. Mutations in this gene are associated with the formation of tumors, including hereditary paraganglioma. Transmission of disease occurs almost exclusively through the paternal allele, suggesting that this locus may be maternally imprinted. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

SDHD links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_003002.4 (SDHD) was described as [Pathogenic] in ClinVar as 6906

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-112086908-A-T is Pathogenic according to our data. Variant chr11-112086908-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 422629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4 linkuse as main transcript	c.1A>T	p.Met1?	start_lost	1/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8 linkuse as main transcript	c.1A>T	p.Met1?	start_lost	1/4	1	NM_003002.4	P1	O14521-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251434

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 10, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 422629). Disruption of the initiator codon has been observed in individuals with head and neck paragangliomas (HNPGLs) or non-HNPGLs (PMID: 11391796, 12782822, 17406045, 17576205, 21945342). This variant is present in population databases (rs104894307, gnomAD 0.002%). This sequence change affects the initiator methionine of the SDHD mRNA. The next in-frame methionine is located at codon 91. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 05, 2019

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19454582, 17576205, 22241717, 15066320, 21945342, 21792967, 29625052) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2022

The p.M1? pathogenic mutation (also known as c.1A>T) is located in coding exon 1 of the SDHD gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This variant was identified in an individual with pheochromocytoma/paraganglioma from the TCGA cohort (Huang KL et al. Cell, 2018 04;173:355-370.e14). Different alterations disrupting this initiation codon (including c.3G>A, c.3G>C, and c.2T>A) have been observed in multiple individuals with pheochromocytomas and/or paragangliomas (Cascón A et al. J. Clin. Endocrinol. Metab. 2009 May;94(5):1701-5; Ben Aim L et al. J. Med. Genet. 2019 Aug;56(8):513-520; Badenhop RF et al. Genes Chromosomes Cancer. 2001 Jul;31(3):255-63; Lee SC et al. Laryngoscope, 2003 Jun;113:1055-8; Ma RC et al. Hong Kong Med J, 2007 Apr;13:151-4; Zha Y et al. Laryngoscope. 2011 Aug;121(8); Wang CP et al. Oral Oncol. 2012 Feb;48(2):125-9; Neumayer C et al. Eur J Clin Invest 2007 Jul;37(7):544-51; Ambry internal data). 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

0.52

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.34

T;.;.;.;.;.;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

D;D;D;D;D;.;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.99

D;D;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;N;N

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

D;.;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D

Polyphen

0.96

D;.;.;.;.;.;.

Vest4

0.75

MutPred

0.95

Loss of MoRF binding (P = 0.0894);Loss of MoRF binding (P = 0.0894);Loss of MoRF binding (P = 0.0894);Loss of MoRF binding (P = 0.0894);Loss of MoRF binding (P = 0.0894);Loss of MoRF binding (P = 0.0894);Loss of MoRF binding (P = 0.0894);

MVP

0.99

ClinPred

1.0

GERP RS

5.2

Varity_R

0.97

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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