rs397514034

Positions:

• chr11-112087895-ATC-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.94_95del​(p.Ala33IlefsTer35) variant causes a frameshift change involving the alteration of a non-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 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.12

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 42 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112087895-ATC-A is Pathogenic according to our data. Variant chr11-112087895-ATC-A is described in ClinVar as [Pathogenic]. Clinvar id is 6908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112087895-ATC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4	c.94_95del	p.Ala33IlefsTer35	frameshift_variant	2/4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.94_95del	p.Ala33IlefsTer35	frameshift_variant	2/4	1	NM_003002.4	ENSP00000364699	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

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

Dec 14, 2022

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6908). This variant is also known as F933>X67. This premature translational stop signal has been observed in individual(s) with pheochromocytoma and/or paraganglioma (PMID: 11323050, 19072999). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Ala33Ilefs*35) 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

Apr 14, 2001

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 31, 2017

This deletion of two nucleotides in SDHD is denoted c.94_95delTC at the cDNA level and p.Ala33IlefsX35 (A33IfsX35) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TATC[delTC]AGCA. The deletion causes a frameshift which changes an Alanine to an Isoleucine at codon 33, and creates a premature stop codon at position 35 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. SDHD c.94_95delTC, also reported as SDHD F933>X67, has been identified in several individuals with pheochromocytoma and/or paraganglioma, and was found to segregate with disease in at least two families (Astuti 2001, Marvin 2009, van Nederveen 2009, Buffet 2012, Kim 2014). Based on currently available information, we consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2022

The c.94_95delTC pathogenic mutation, located in coding exon 2 of the SDHD gene, results from a deletion of two nucleotides at nucleotide positions 94 to 95, causing a translational frameshift with a predicted alternate stop codon (p.A33Ifs*35). This pathogenic mutation, referred to as F933>X67, has been reported in a 15 year old patient with a personal and family history of head and neck paragangliomas (Marvin et al. Head and Neck. 2009.31(5): 689-694). This pathogenic mutation was also reported in a family diagnosed with multiple pheochromocytomas (Astuti et al. Lancet. 2001. 357(9263):1181-1182). 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)		0.050		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: rs397514034; hg19: chr11-111958619;