rs104894310

Positions:

• chr11-112086921-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003002.4(SDHD):​c.14G>A​(p.Trp5Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHD NM_003002.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.554

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 47 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112086921-G-A is Pathogenic according to our data. Variant chr11-112086921-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112086921-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4	c.14G>A	p.Trp5Ter	stop_gained	1/4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.14G>A	p.Trp5Ter	stop_gained	1/4	1	NM_003002.4	ENSP00000364699	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

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

Labcorp Genetics (formerly Invitae), Labcorp

Oct 02, 2021

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 6916). This premature translational stop signal has been observed in individual(s) with clinical features of paraganglioma-pheochromocytoma syndrome (PMID: 12000816, 25819804, 30050099). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp5*) in the SDHD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHD are known to be pathogenic (PMID: 19454582, 19802898). -

Paragangliomas 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 09, 2002

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2024

The p.W5* pathogenic mutation (also known as c.14G>A), located in coding exon 1 of the SDHD gene, results from a G to A substitution at nucleotide position 14. This changes the amino acid from a tryptophan to a stop codon within coding exon 1. This mutation has been observed in multiple individuals with a personal and/or family history that is consistent with SDHD-related paraganglioma-pheochromocytoma syndrome (Neumann HP et al. N Engl J Med, 2002 May;346:1459-66; Richter S et al. Genet Med, 2019 Mar;21:705-717; White G et al. Endocr Connect, 2022 Feb;11; Ambry internal data). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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	Uncertain	0.090
CADD	Pathogenic	35
DANN	Benign	0.95
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.039
FATHMM_MKL	Benign	0.38	N
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.67
GERP RS		2.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs104894310; hg19: chr11-111957645;