NM_003002.4:c.3G>C

Variant names:

• chr11-112086910-G-C
• rs80338842
• NM_003002.4:c.3G>C

Variant summary

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

The NM_003002.4(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 NM_003002.4 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]

ENSG00000255292 (HGNC:):

TIMM8B (HGNC:11818): (translocase of inner mitochondrial membrane 8 homolog B) This gene encodes a member of a well-conserved family of proteins with similarity to yeast Tim mitochondrial import proteins. This gene is encoded by a nuclear gene and is transported into the intermembrane space of the mitochondrion. When formed into complexes, these proteins guide membrane-spanning proteins across the mitochondrial intermembrane space before they are added into the mitochondrial inner membrane. This gene is adjacent to succinate dehydrogenase, subunit D (SDHD), in which mutations have been found in affected members of families with hereditary paraganglioma.[provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 26 pathogenic variants. Next in-frame start position is after 91 codons. Genomic position: 112088968. Lost 0.565 part of the original CDS.
• PS1: Another start lost variant in NM_003002.4 (SDHD) was described as [Pathogenic] in Lovd
• 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 rank	MANE	Protein	UniProt
SDHD	NM_003002.4	c.3G>C	p.Met1?	start_lost	Exon 1 of 4	ENST00000375549.8	NP_002993.1
TIMM8B	NM_012459.4	c.-187C>G		upstream_gene_variant		ENST00000504148.3	NP_036591.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.3G>C	p.Met1?	start_lost	Exon 1 of 4	1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.3G>C		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000456434.1
TIMM8B	ENST00000504148.3	c.-187C>G		upstream_gene_variant		1	NM_012459.4	ENSP00000422122.2

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

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 21, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Jun 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the SDHD mRNA. The next in-frame methionine is located at codon 91. This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 6906). For these reasons, this variant has been classified as Pathogenic. -

Paragangliomas 1 Pathogenic:1

Jul 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 26, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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;