11-112086910-G-C

Position:

• chr11-112086910-G-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The ENST00000375549.8(SDHD):​c.3G>C​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 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 ENST00000375549.8 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 5.01

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000375549.8 (SDHD) was described as [Pathogenic] in ClinVar as 579968
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112086910-G-C is Pathogenic according to our data. Variant chr11-112086910-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 6906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112086910-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4	c.3G>C	p.Met1?	start_lost	1/4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.3G>C	p.Met1?	start_lost	1/4	1	NM_003002.4	ENSP00000364699	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 21, 2019	The c.3G>C (p.Met1?) variant in SDHD has been identified to be a Chinese founder variant and has been reported in at least 13 Chinese individuals with hereditary paragangliomas and/or pheochromocytomas (PGL/PCC), segregating with disease in at least 10 relatives in these families (Badenhop 2001, Lee 2003, Ma 2007, Zha 2011, Wang 2012, Zhu 2015). This variant has also been reported by other clinical laboratories in Clinvar (Variation ID: 6906) and was absent from large population studies. The p.Met1? variant alters the evolutionary conserved initiation codon of the SDHD gene and is predicted to disrupt translation. The precise effect on the protein cannot be predicted, as this variant may lead to no protein synthesis or the activation of an upstream translation initiation codon, resulting in an aberrant protein. Additionally, other variants at this position, resulting in the same impact on the protein, have been reported in individuals with PGL/PCC (Burnichon 2009, Cascon 2009, Neumayer 2007, Piccini 2012, Riemann 2004). Heterozygous loss of function of the SDHD gene is an established disease mechanism in individuals with hereditary PGL/PCC. In summary, this variant meets criteria to be classified as pathogenic for hereditary PGL/PCC in an autosomal dominant manner based upon multiple occurrences in affected individuals, segregation studies, absence from the general population, and the predicted impact on protein. ACMG/AMP criteria applied: PS4; PVS1_Moderate, PM2, PP1_Strong. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

Disruption of the initiator codon has been observed in individual(s) with clinical features of SDHD-related conditions (PMID: 11391796, 12782822, 15066320, 17576205, 19351833, 19454582, 21792967, 21945342, 22241717). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6906). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SDHD mRNA. The next in-frame methionine is located at codon 91. -

Paragangliomas 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2001

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 22, 2021

The p.M1? pathogenic mutation (also known as c.3G>C) is located in coding exon 1 of the SDHD gene and results from a G to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. This mutation has been reported in multiple Asian families affected with early onset paragangliomas, and haplotype analysis has identified it as a Chinese founder mutation (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; Ting KR et al. Hered Cancer Clin Pract 2020 Dec;18(1):24). This alteration is also denoted as p.M1I throughout the literature. In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.;.;.;.;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;.;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A
PROVEAN	Benign	-1.4	N;.;N;D;N;N;N
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.;.
Vest4		0.80
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.0211);Gain of catalytic residue at M1 (P = 0.0211);Gain of catalytic residue at M1 (P = 0.0211);Gain of catalytic residue at M1 (P = 0.0211);Gain of catalytic residue at M1 (P = 0.0211);Gain of catalytic residue at M1 (P = 0.0211);Gain of catalytic residue at M1 (P = 0.0211);
MVP		0.98
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.96
gMVP		0.67

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

Other links and lift over

dbSNP: rs80338842; hg19: chr11-111957634;