rs878854590

Positions:

• chr11-112088868-TG-T

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.173del​(p.Gly58AlafsTer28) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,856 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G58G) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SDHD NM_003002.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.75

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112088868-TG-T is Pathogenic according to our data. Variant chr11-112088868-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 239461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.173del	p.Gly58AlafsTer28	frameshift_variant, splice_region_variant	3/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.173del	p.Gly58AlafsTer28	frameshift_variant, splice_region_variant	3/4	1	NM_003002.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459856 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Invitae

Mar 08, 2016

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, truncating variants in SDHD are known to be pathogenic (PMID: 19802898, 19454582). This sequence change deletes 1 nucleotide from exon 3 of the SDHD mRNA (c.173delG), causing a frameshift at codon 58. This creates a premature translational stop signal (p.Gly58Alafs*28) and is expected to result in an absent or disrupted protein product. -

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C3494181:Paragangliomas 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 08, 2016

This sequence change deletes 1 nucleotide from exon 3 of the SDHD mRNA (c.173delG), causing a frameshift at codon 58. This creates a premature translational stop signal (p.Gly58Alafs*28) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in SDHD are known to be pathogenic (PMID: 19802898, 19454582). 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

Jun 16, 2023

The c.173delG pathogenic mutation, located in coding exon 3 of the SDHD gene, results from a deletion of one nucleotide at nucleotide position 173, causing a translational frameshift with a predicted alternate stop codon (p.G58Afs*28). A different alteration (c.171delT) resulting in the same frameshift has been reported in a cohort of individuals with personal and/or family histories of pheochromocytoma/paraganglioma (Andrews KA et al. J Med Genet, 2018 Jun;55:384-394). 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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs878854590; hg19: chr11-111959592;