11-112094923-C-A

Position:

chr11-112094923-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The NM_003002.4(SDHD):c.433C>A(p.His145Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,458,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

SDHD
NM_003002.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.96

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]

SDHD links:

ENSG00000255292 (HGNC:):

ENSG00000255292 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a chain Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial (size 102) in uniprot entity DHSD_HUMAN there are 30 pathogenic changes around while only 2 benign (94%) in NM_003002.4

BP4

Computational evidence support a benign effect (MetaRNN=0.41076955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHD	NM_003002.4 linkuse as main transcript	c.433C>A	p.His145Asn	missense_variant	4/4	ENST00000375549.8	NP_002993.1	O14521-1A0A0S2Z4J3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8 linkuse as main transcript	c.433C>A	p.His145Asn	missense_variant	4/4	1	NM_003002.4	ENSP00000364699.3		O14521-1
ENSG00000255292	ENST00000532699.1 linkuse as main transcript	n.314+5912C>A		intron_variant		3		ENSP00000456434.1		H3BRW5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000806

AC:

AN:

248184

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1458918

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

725798

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 09, 2023

This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 145 of the SDHD protein (p.His145Asn). This variant is present in population databases (rs121908984, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of Cowden syndrome and a personal and/or family history of head and neck paraganglioma (HNPGL) and/or pheochromocytoma and paranganglioma (PPGL) (PMID: 18678321, 21979946, 29386252). ClinVar contains an entry for this variant (Variation ID: 6918). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SDHD function (PMID: 18678321). 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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 12, 2023

- -

Cowden syndrome 3

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Aug 01, 2008

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2022

The p.H145N variant (also known as c.433C>A), located in coding exon 4 of the SDHD gene, results from a C to A substitution at nucleotide position 433. The histidine at codon 145 is replaced by asparagine, an amino acid with similar properties. In a study of individuals with clinical manifestations suggestive of Cowden Syndrome but who were negative for any pathogenic PTEN gene variants, the SDHD p.H145N variant was identified in a 53 year old female diagnosed with breast carcinoma and renal cell carcinoma and who had no family history of cancer. It was not detected in 700 control samples. Functional studies indicated that the p.H145N variant led to mitochondrial dysfunction and the activation of the MAPK pathway which is usually seen with PTEN dysfunction (Ni Y et al. Am. J. Hum. Genet., 2008 Aug;83:261-8; Ni Y et al. Hum. Mol. Genet., 2012 Jan;21:300-10). This amino acid position is well conserved in available vertebrate species. 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

0.14

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Uncertain

0.58

D;.

Eigen

Benign

-0.15

Eigen_PC

Benign

0.034

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.41

T;T

MetaSVM

Uncertain

0.68

MutationAssessor

Benign

-0.41

N;.

PrimateAI

Uncertain

0.76

PROVEAN

Benign

0.020

N;N

REVEL

Uncertain

0.49

Sift

Benign

0.63

T;T

Sift4G

Benign

0.69

T;T

Polyphen

0.0010

B;.

Vest4

0.70

MutPred

0.81

Loss of stability (P = 0.1124);.;

MVP

0.84

MPC

0.21

ClinPred

0.12

GERP RS

4.8

Varity_R

0.085

gMVP

0.86

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over