11-112088952-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4BP6

The NM_003002.4(SDHD):​c.255G>T​(p.Leu85Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SDHD
NM_003002.4 missense

Scores

1
8
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1O:1

Conservation

PhyloP100: 1.77
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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;
BP4
Computational evidence support a benign effect (MetaRNN=0.32012275).
BP6
Variant 11-112088952-G-T is Benign according to our data. Variant chr11-112088952-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135198.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, not_provided=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SDHDNM_003002.4 linkuse as main transcriptc.255G>T p.Leu85Phe missense_variant 3/4 ENST00000375549.8 NP_002993.1 O14521-1A0A0S2Z4J3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SDHDENST00000375549.8 linkuse as main transcriptc.255G>T p.Leu85Phe missense_variant 3/41 NM_003002.4 ENSP00000364699.3 O14521-1
ENSG00000255292ENST00000532699.1 linkuse as main transcriptn.255G>T non_coding_transcript_exon_variant 3/63 ENSP00000456434.1 H3BRW5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461758
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727188
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 08, 2022In 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 135198). This variant has not been reported in the literature in individuals affected with SDHD-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 85 of the SDHD protein (p.Leu85Phe). -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoFeb 13, 2024The SDHD c.255G>T (p.Leu85Phe) variant has been reported in the published literature in an individual with paraganglioma and follicular lymphoma (PMID: 34877445 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 14, 2020This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not specified Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.040
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.74
D;.;.;.;.;.
Eigen
Benign
-0.12
Eigen_PC
Benign
-0.0015
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.82
T;T;T;T;.;T
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.32
T;T;T;T;T;T
MetaSVM
Uncertain
0.75
D
MutationAssessor
Benign
1.1
L;L;.;.;L;.
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-1.8
N;.;N;N;N;N
REVEL
Uncertain
0.61
Sift
Benign
0.19
T;.;T;T;T;T
Sift4G
Benign
0.22
T;T;T;T;T;T
Polyphen
0.053
B;.;.;.;.;.
Vest4
0.27
MutPred
0.50
Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;
MVP
0.90
MPC
0.21
ClinPred
0.60
D
GERP RS
4.1
Varity_R
0.076
gMVP
0.68

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199517389; hg19: chr11-111959676; API