rs761953172

chr11-112094943-A-Cchr11-112094943-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP4

The NM_003002.4(SDHD):c.453A>C(p.Lys151Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,458,796 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K151R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.74

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]

ACMG classification

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 64 pathogenic changes around while only 7 benign (90%) in NM_003002.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.33898187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.453A>C	p.Lys151Asn	missense_variant	4/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.453A>C	p.Lys151Asn	missense_variant	4/4	1	NM_003002.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248046 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134846

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: 0.0000117 AC: 17 AN: 1458796 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 725788

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: 0.0000126

Gnomad4 OTH exome AF: 0.0000499

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000508 Hom.: 0

ExAC AF: 0.0000166 AC: 2

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2023

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 151 of the SDHD protein (p.Lys151Asn). This variant is present in population databases (rs761953172, gnomAD 0.002%). 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: 239472). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 11, 2020

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as p.K95N -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The p.K151N variant (also known as c.453A>C), located in coding exon 4 of the SDHD gene, results from an A to C substitution at nucleotide position 453. The lysine at codon 151 is replaced by asparagine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.11	T;T
Sift4G	Benign	0.25	T;D
Polyphen		0.30	B;.
Vest4		0.20
MutPred		0.61		Loss of methylation at K151 (P = 0.0067);.;
MVP		0.87
MPC		0.39
ClinPred		0.23	T
GERP RS		2.4
Varity_R		0.15
gMVP		0.89

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: rs761953172; hg19: chr11-111965667;