Variant rs121908983 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM4_SupportingPP5_Moderate

The NM_003002.4(SDHD):c.278_280del(p.Tyr93del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SDHD
NM_003002.4 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.54

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity DHSD_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_003002.4

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_003002.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 11-112088973-CTAT-C is Pathogenic according to our data. Variant chr11-112088973-CTAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 6905.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4 linkuse as main transcript	c.278_280del	p.Tyr93del	inframe_deletion	3/4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8 linkuse as main transcript	c.278_280del	p.Tyr93del	inframe_deletion	3/4	1	NM_003002.4	ENSP00000364699	P1	O14521-1

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Paragangliomas 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2001

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2023

The c.278_280delATT pathogenic mutation (also known as p.Y93del) is located in coding exon 3 of the SDHD gene. This pathogenic mutation results from an in-frame ATT deletion at nucleotide positions 278 to 280. This results in the in-frame deletion of a tyrosine at codon 93. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with SDHD-related disease (Chen H et al. J Cancer Res Clin Oncol, 2017 Jun;143:953-960; Shi C et al. J Endocr Soc, 2023 Aug;7:bvad093; Ambry internal data). Another alteration at the same codon, c.276_278del (p.Y93del), has also been detected in individuals diagnosed with paragangliomas (Badenhop RF et al. Genes Chromosomes Cancer, 2001 Jul;31:255-63; Andrews KA et al. J Med Genet, 2018 06;55:384-394). Based on internal structural analysis, this alteration is more destabilizing to SDHD than several internally pathogenic variants at the same position and nearby (Ambry internal data, Zhou Q et al. Protein Cell, 2011 Jul;2:531-42). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing