11-112093080-G-A

Variant names:

• chr11-112093080-G-A
• rs1865776060
• NM_003002.4:c.315-1725G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001276506.2(SDHD):​c.315G>A​(p.Trp105*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SDHD NM_001276506.2 stop_gained, splice_region
• Scores: Splicing: ADA: 0.00001674
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.243
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• pheochromocytoma/paraganglioma syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Carney-Stratakis syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• mitochondrial complex 2 deficiency, nuclear type 3

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• mitochondrial complex II deficiency

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intestinal cancer

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000255292 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001276506.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHD	NM_003002.4	MANE Select	c.315-1725G>A		intron	N/A	NP_002993.1	O14521-1
	SDHD	NM_001276506.2		c.315G>A	p.Trp105*	stop_gained splice_region	Exon 4 of 5	NP_001263435.1	O14521-4
	SDHD	NM_001276504.2		c.198-1725G>A		intron	N/A	NP_001263433.1	O14521-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHD	ENST00000375549.8	TSL:1 MANE Select	c.315-1725G>A		intron	N/A	ENSP00000364699.3	O14521-1
	SDHD	ENST00000528048.5	TSL:1	c.170-1725G>A		intron	N/A	ENSP00000436217.1	O14521-3
	ENSG00000255292	ENST00000532699.1	TSL:3	n.314+4069G>A		intron	N/A	ENSP00000456434.1	H3BRW5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 105870 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 65664

African (AFR) AF: 0.00 AC: 0 AN: 1386

American (AMR) AF: 0.00 AC: 0 AN: 5756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4680

East Asian (EAS) AF: 0.00 AC: 0 AN: 816

South Asian (SAS) AF: 0.00 AC: 0 AN: 28766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 422

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53400

Other (OTH) AF: 0.00 AC: 0 AN: 4252

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	7.6
DANN	Benign	0.76
Eigen	Benign	-0.77
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0049	N
PhyloP100		0.24
Mutation Taster		=65/135	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1865776060;

hg19: chr11-111963804;