11-112088896-ACT-GCC

Position:

• chr11-112088896-ACT-GCC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_003002.4(SDHD):​c.199_201delACTinsGCC​(p.Thr67Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.88

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a transmembrane_region Helical (size 21) in uniprot entity DHSD_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_003002.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4	c.199_201delACTinsGCC	p.Thr67Ala	missense_variant		ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.199_201delACTinsGCC	p.Thr67Ala	missense_variant		1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.199_201delACTinsGCC		non_coding_transcript_exon_variant	3/6	3		ENSP00000456434.1

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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 13, 2019

This sequence change replaces threonine with alanine at codon 67 of the SDHD protein (p.Thr67Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an SDHD-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555186981; hg19: chr11-111959620;