rs1306475361

chr11-112088866-G-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_003002.4(SDHD):c.170-1G>T variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SDHD NM_003002.4 splice_acceptor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.48

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 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.6, offset of 11, new splice context is: tttttgtatctggctccaAGgct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-112088866-G-T is Pathogenic according to our data. Variant chr11-112088866-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 438434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112088866-G-T is described in Lovd as [Likely_pathogenic]. Variant chr11-112088866-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.170-1G>T		splice_acceptor_variant		ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.170-1G>T		splice_acceptor_variant		1	NM_003002.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251124 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135712

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 20, 2023	This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism of disease. This prediction has been confirmed by functional studies (PMID: 12509798, 29545045). This variant has been reported in multiple individuals with paragangliomas (PMID: 12509798, 18551016, 12114404, 19075037, 22566194, 29545045, 30877234, 32472550). This variant is present in 1/251124 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant has been reported to co-segregate with disease in more than one family (PMID: 12509798, 18551016, 32472550). -
Pathogenic, no assertion criteria provided	research	Section on Medical Neuroendocrinolgy, National Institutes of Health	-	- -

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

Jan 11, 2024

This sequence change affects an acceptor splice site in intron 2 of the SDHD gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHD are known to be pathogenic (PMID: 19454582, 19802898). This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with SDHD-related conditions (PMID: 12114404, 12509798, 18551016, 19075037, 22566194, 29545045, 30050099, 30877234). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438434). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2020

The c.170-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 3 of the SDHD gene. This alteration has been identified in numerous patients from multiple ethnic groups with unilateral or bilateral carotid body tumors, both with and without a family history of pheochromocytomas and/or paragangliomas (Dannenberg H et al. Clin. Cancer Res. 2002 Jul;8:2061-6; Persu A et al. J. Hypertens. 2008 Jul;26:1395-401; Renard L et al. Head Neck. 2003 Feb;25:146-51; Zuo Y et al. Urology. 2018 06;116:63-67; Santi R et al. Anticancer Res. 2017 02;37:805-812; Piccini V et al. Endocr. Relat. Cancer. 2012 Apr;19:149-55; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Astrom K et al. Hum. Genet. 2003 Aug;113:228-37; Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar;91:827-36). This alteration was also identified in a patient with a glomus tumor (Mannelli M et al. Ann. N. Y. Acad. Sci. 2006 Aug;1073:183-9), a patient with bilateral carotid body tumors and a primary mediastinal paraganglioma (Ghayee HK et al. Endocr. Relat. Cancer. 2009 Mar;16:291-9;), and patients with cervical paragangliomas (Bauters C et al. J. Med. Genet. 2003 Jun;40:e75). Of note, this alteration is also designated as IVS2-1G>T in the published literature. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	33
Dann	Uncertain	0.98
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 12
DS_AL_spliceai		0.85		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1306475361; hg19: chr11-111959590;