rs876658477

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_003002.4(SDHD):​c.320T>C​(p.Leu107Pro) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Consequence

SDHD
NM_003002.4 missense

Scores

12
3
3

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.68
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a transmembrane_region Helical (size 20) in uniprot entity DHSD_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_003002.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.914
PP5
Variant 11-112094810-T-C is Pathogenic according to our data. Variant chr11-112094810-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1728924.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SDHDNM_003002.4 linkc.320T>C p.Leu107Pro missense_variant Exon 4 of 4 ENST00000375549.8 NP_002993.1 O14521-1A0A0S2Z4J3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SDHDENST00000375549.8 linkc.320T>C p.Leu107Pro missense_variant Exon 4 of 4 1 NM_003002.4 ENSP00000364699.3 O14521-1
ENSG00000255292ENST00000532699.1 linkn.314+5799T>C intron_variant Intron 3 of 5 3 ENSP00000456434.1 H3BRW5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1
May 30, 2024
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.L107P variant (also known as c.320T>C), located in coding exon 4 of the SDHD gene, results from a T to C substitution at nucleotide position 320. The leucine at codon 107 is replaced by proline, an amino acid with similar properties. This variant has been observed in multiple individuals with a personal and/or family history that is consistent with SDHD-associated disease (Ambry internal data). This variant was identified in a family with multiple cases of carotid body tumors (PGLs) and was shown to segregate with disease in the affected family members through the paternal line (Otani N et al. Jpn. J. Clin. Oncol., 2017 Dec;47:1193-1197). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
D;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.84
T;T
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.91
D;D
MetaSVM
Pathogenic
1.1
D
PrimateAI
Benign
0.46
T
PROVEAN
Pathogenic
-5.0
D;D
REVEL
Pathogenic
0.92
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.0060
D;D
Polyphen
0.99
D;.
Vest4
0.77
MutPred
0.67
Loss of stability (P = 0.0278);.;
MVP
0.94
MPC
0.94
ClinPred
0.98
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.96
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-111965534; API