rs104894305

Positions:

• chr11-112087899-C-A
• chr11-112087899-C-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.95C>A​(p.Ser32*) 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:7
• Conservation: PhyloP100: 1.97

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]

ENSG00000255292 (HGNC:):

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 42 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112087899-C-A is Pathogenic according to our data. Variant chr11-112087899-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 6901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112087899-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4	c.95C>A	p.Ser32*	stop_gained	2/4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.95C>A	p.Ser32*	stop_gained	2/4	1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.95C>A		non_coding_transcript_exon_variant	2/6	3		ENSP00000456434.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paragangliomas 1 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	May 15, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 09, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Aug 01, 2019	This variant has been reported in the literature in several patients with paragangliomas (Milunsky 2001). This variant creates a premature termination codon. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of SDHD is an established mechanism of disease (Burnichon 2009, Ricketts 2010). This variant is not present in population databases (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. -

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 05, 2022

ClinVar contains an entry for this variant (Variation ID: 6901). 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 disrupt the consensus splice site. This premature translational stop signal has been observed in individuals with paraganglioma (PMID: 23433498). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser32*) 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). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 20, 2024

PP4, PM2, PS4_moderate, PVS1 -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2022

The p.S32* pathogenic mutation (also known as c.95C>A), located in coding exon 2 of the SDHD gene, results from a C to A substitution at nucleotide position 95. This changes the amino acid from a serine to a stop codon within coding exon 2. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with SDHD-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Section on Medical Neuroendocrinolgy, National Institutes of Health

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Benign	0.75	D
Vest4		0.92
GERP RS		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: -42

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894305; hg19: chr11-111958623;