chr11-112094933-GC-TT

Variant names:

• chr11-112094933-GC-TT
• rs1555187635
• NM_003002.4:c.443_444delGCinsTT

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3 PP5_Moderate

The NM_003002.4(SDHD):​c.443_444delGCinsTT​(p.Gly148Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G148D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.58
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• pheochromocytoma/paraganglioma syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Carney-Stratakis syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• mitochondrial complex II deficiency, nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• mitochondrial complex 2 deficiency, nuclear type 3

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• mitochondrial complex II deficiency

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intestinal cancer

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000255292 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 11-112094933-GC-TT is Pathogenic according to our data. Variant chr11-112094933-GC-TT is described in ClinVar as Pathogenic. ClinVar VariationId is 480776.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHD	NM_003002.4	c.443_444delGCinsTT	p.Gly148Val	missense_variant		ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.443_444delGCinsTT	p.Gly148Val	missense_variant		1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.314+5922_314+5923delGCinsTT		intron_variant	Intron 3 of 5	3		ENSP00000456434.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

May 03, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.443_444delGCinsTT pathogenic mutation (also known as p.G148V), located in coding exon 4 of the SDHD gene, results from an in-frame deletion of GC and insertion of TT between nucleotide positions 443 and 444. This results in the substitution of a glycine for a valine residue at codon 148, an amino acid with dissimilar properties. This variant was reported in individual(s) with features consistent with SDHD-related hereditary pheochromocytoma-paraganglioma (Ambry internal data). Other variant(s) resulting in the same amino acid change, p.Gly148Val (c.443G>T), have been identified in individual(s) with features consistent with SDHD-related hereditary pheochromocytoma-paraganglioma (Neumann et al. JAMA. 2004;292:943-951). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6

Splicing

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

Other links and lift over

dbSNP: rs1555187635; hg19: chr11-111965657;