rs121908984

Positions:

• chr11-112094923-C-A
• chr11-112094923-C-T

Variant summary

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

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H145Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.96

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 hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_003002.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.41076955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.433C>A	p.His145Asn	missense_variant	4/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.433C>A	p.His145Asn	missense_variant	4/4	1	NM_003002.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248184 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134896

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: 29 AN: 1458918 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 14 AN XY: 725798

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.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

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

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	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Uncertain	0.58	D;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	-0.41	N;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.76	T
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	T
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

Other links and lift over

dbSNP: rs121908984; hg19: chr11-111965647;