ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.143A>T (p.Asp48Val)

gnomAD frequency: 0.00001  dbSNP: rs202101384
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000470589 SCV000553986 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 48 of the SDHB protein (p.Asp48Val). This variant is present in population databases (rs202101384, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive mitochondrial complex II deficiency (PMID: 22972948, 26642834, 26925370, 27604842). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 39584). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SDHB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 22972948). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001011583 SCV001171920 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-24 criteria provided, single submitter clinical testing The c.143A>T (p.D48V) alteration is located in exon 2 (coding exon 2) of the SDHB gene. This alteration results from a A to T substitution at nucleotide position 143, causing the aspartic acid (D) at amino acid position 48 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx RCV001578167 SCV001805706 pathogenic not provided 2022-02-03 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant has only been reported/observed in association with autosomal recessive complex II deficiency and has not, to our knowledge, been associated with autosomal dominant hereditary paraganglioma/pheochromocytoma syndrome; This variant is associated with the following publications: (PMID: 22972948, 27556822, 29282712, 26642834, 27159321, 26968897, 27604842, 23174333, 29019354, 34426522, 31589614, 33726816, 26925370)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001578167 SCV002552252 likely pathogenic not provided 2023-08-15 criteria provided, single submitter clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV003315403 SCV004015257 likely pathogenic Paragangliomas 4 2023-07-07 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 48 of the SDHB protein (p.Asp48Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs202101384, ExAC 0.04%). This variant has been observed as homozygous or in combination with other SDHB variant in individuals affected with autosomal recessive mitochondrial complex II deficiency (PMID: 22972948, 27556822, 29282712, 26642834, 27159321, 26968897, 27604842, 23174333, 29019354, 34426522, 31589614, 33726816, 26925370). However, this variant has not been observed in individuals with pheochromocytoma (PCC) or paraganglioma (PGL). ClinVar contains an entry for this variant (Variation ID: 39584). In silico analysis supports that this missense variant has a deleterious effect on protein structure/function also an experimental study shown the affected protein function . In summary, this variant has been observed in individuals with mitochondrial complex II deficiency and has been shown to affect protein function. The currently available evidence indicates that the variant is pathogenic, Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV003473248 SCV004203011 pathogenic Gastrointestinal stromal tumor 2023-06-05 criteria provided, single submitter clinical testing
OMIM RCV000032784 SCV000056548 pathogenic Mitochondrial complex 2 deficiency, nuclear type 4 2012-09-01 no assertion criteria provided literature only
Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence, RCV001249469 SCV001370765 uncertain significance Mitochondrial complex II deficiency, nuclear type 1 no assertion criteria provided clinical testing

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