Submissions for variant NM_003002.4(SDHD):c.118A>C (p.Ile40Leu)

dbSNP: rs146276662

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202919	SCV000257881	uncertain significance	Paragangliomas 1	2015-03-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003103746	SCV000287813	uncertain significance	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 40 of the SDHD protein (p.Ile40Leu). This variant is present in population databases (rs146276662, gnomAD 0.005%). This missense change has been observed in individual(s) with Cowden or Cowden-like syndrome (PMID: 22829200). ClinVar contains an entry for this variant (Variation ID: 218581). 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.
Ambry Genetics	RCV000575031	SCV000675109	likely benign	Hereditary cancer-predisposing syndrome	2020-08-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV001105197	SCV001262127	likely benign	Hereditary pheochromocytoma-paraganglioma	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV001105197	SCV004845030	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 40 of the SDHD protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 Cowden-like syndrome (PMID: 22829200), or head-neck paraganglioma (PMID: 19351833). This variant has been identified in 7/251478 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.