rs1555186671

Variant names:

• chr11-112086935-G-A
• rs1555186671
• NM_003002.4:c.28G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-112086935-G-A
• chr11-112086935-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003002.4(SDHD):​c.28G>A​(p.Val10Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.0700

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:):

TIMM8B (HGNC:11818): (translocase of inner mitochondrial membrane 8 homolog B) This gene encodes a member of a well-conserved family of proteins with similarity to yeast Tim mitochondrial import proteins. This gene is encoded by a nuclear gene and is transported into the intermembrane space of the mitochondrion. When formed into complexes, these proteins guide membrane-spanning proteins across the mitochondrial intermembrane space before they are added into the mitochondrial inner membrane. This gene is adjacent to succinate dehydrogenase, subunit D (SDHD), in which mutations have been found in affected members of families with hereditary paraganglioma.[provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16635588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHD	NM_003002.4	c.28G>A	p.Val10Ile	missense_variant	Exon 1 of 4	ENST00000375549.8	NP_002993.1
TIMM8B	NM_012459.4	c.-212C>T		upstream_gene_variant		ENST00000504148.3	NP_036591.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.28G>A	p.Val10Ile	missense_variant	Exon 1 of 4	1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.28G>A		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000456434.1
TIMM8B	ENST00000504148.3	c.-212C>T		upstream_gene_variant		1	NM_012459.4	ENSP00000422122.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

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 Uncertain:1

May 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 10 of the SDHD protein (p.Val10Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SDHD-related conditions. ClinVar contains an entry for this variant (Variation ID: 465232). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHD protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mitochondrial complex 2 deficiency, nuclear type 3 Uncertain:1

May 28, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V10I variant (also known as c.28G>A), located in coding exon 1 of the SDHD gene, results from a G to A substitution at nucleotide position 28. The valine at codon 10 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.20	T;.;.;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.60	T;T;T;T;T;.;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.0	N;N;.;N;.;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.11	N;.;N;N;N;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.049	D;.;D;T;D;T;T
Sift4G	Benign	0.15	T;T;T;T;T;T;T
Polyphen		0.014	B;.;.;.;.;.;.
Vest4		0.13
MutPred		0.34		Loss of MoRF binding (P = 0.0917);Loss of MoRF binding (P = 0.0917);Loss of MoRF binding (P = 0.0917);Loss of MoRF binding (P = 0.0917);Loss of MoRF binding (P = 0.0917);Loss of MoRF binding (P = 0.0917);Loss of MoRF binding (P = 0.0917);
MVP		0.92
MPC		0.15
ClinPred		0.071	T
GERP RS		1.1
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.032
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1555186671; hg19: chr11-111957659;