11-112087952-C-G

Variant names:

• chr11-112087952-C-G
• rs779249550
• NM_003002.4:c.148C>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_003002.4(SDHD):​c.148C>G​(p.His50Asp) variant causes a missense change involving the alteration of a non-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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H50R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 3.35

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]

ENSG00000255292 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846
• PP5: Variant 11-112087952-C-G is Pathogenic according to our data. Variant chr11-112087952-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 431847.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHD	NM_003002.4	c.148C>G	p.His50Asp	missense_variant	Exon 2 of 4	ENST00000375549.8	NP_002993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHD	ENST00000375549.8	c.148C>G	p.His50Asp	missense_variant	Exon 2 of 4	1	NM_003002.4	ENSP00000364699.3
ENSG00000255292	ENST00000532699.1	n.148C>G		non_coding_transcript_exon_variant	Exon 2 of 6	3		ENSP00000456434.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251456 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135906

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Uncertain:2

Mar 24, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces histidine with aspartic acid at codon 50 of the SDHD protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with paraganglioma (ClinVar Variation ID: 431847). This variant has been identified in 1/251456 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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Section on Medical Neuroendocrinolgy, National Institutes of Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

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Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Pathogenic:1

Sep 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 50 of the SDHD protein (p.His50Asp). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with paraganglioma (PMID: 34906457; internal data). ClinVar contains an entry for this variant (Variation ID: 431847). Invitae Evidence 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 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

May 19, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The H50D variant has previously been reported in at least one individual with bilateral carotid body paragangliomas (Kung and Oh, 2011). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The H50D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on currently available evidence, H50D is a strong candidate for a pathogenic variant. However, the possibility it could be a rare benign variant cannot be excluded. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 04, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H50D variant (also known as c.148C>G), located in coding exon 2 of the SDHD gene, results from a C to G substitution at nucleotide position 148. The histidine at codon 50 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with SDHD-related disease (Ambry internal data). This alteration was reported in a woman with bilateral carotid body paragangliomas (PGLs); her brother and a paternal uncle's daughter were also affected with PGLs. Familial testing determined that the patient's affected brother was positive for this alteration and their unaffected mother was negative, consistent with paternal inheritance (Kung JT, Oh DK. Identification of an Occult Functioning Cardiac Paraganglioma in a Patient with a Novel SDHD Mutation Causing Familial Paraganglioma Syndrome [abstract]. In: The Endocrine Society's 93rd Annual Meeting & Expo. 2011 Jun 4-7; Boston. Abstract P2-664). This amino acid position is highly 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	Benign	0.32
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;.;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;.
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.9	M;M;.;M;.;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.1	D;.;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.018	D;.;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.77
MutPred		0.53		Loss of glycosylation at P53 (P = 0.0815);Loss of glycosylation at P53 (P = 0.0815);Loss of glycosylation at P53 (P = 0.0815);Loss of glycosylation at P53 (P = 0.0815);Loss of glycosylation at P53 (P = 0.0815);Loss of glycosylation at P53 (P = 0.0815);
MVP		0.96
MPC		0.67
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.41
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs779249550; hg19: chr11-111958676;