ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.3286T>A (p.Ser1096Thr) (rs376722127)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000547835 SCV001335312 uncertain significance Rasopathy 2020-03-19 reviewed by expert panel curation The c.3286T>A (p.Ser1096Thr) variant in SOS1 has been observed in 0.01864% (24/128738) of non-Finnish European chromosomes in gnomAD v2.1.1. This variant was seen in several individuals whose clinical presentations lacked clear associations with a RASopathy (PMIDs: 22589294, 26580448, 27153395; Invitae internal data, SCV000659145.1; Baylor internal data; Greenwood Genetic Center internal data). Of note, this variant has also been seen in apparently unaffected parental samples (n=14) evaluated during whole exome sequencing suggesting that this variant may be likely benign; however, these cases were not well-phenotyped and therefore do not meet current requirements for BS2 (BS2 not met; GeneDx internal data). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain.
Invitae RCV000547835 SCV000659145 uncertain significance Rasopathy 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 1096 of the SOS1 protein (p.Ser1096Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs376722127, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 22589294). ClinVar contains an entry for this variant (Variation ID: 477722). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Integrated Genetics/Laboratory Corporation of America RCV000780744 SCV000918256 likely benign not specified 2019-11-04 criteria provided, single submitter clinical testing Variant summary: SOS1 c.3286T>A (p.Ser1096Thr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 251348 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome and Related Conditions phenotype (3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3286T>A has not been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions but was reported in an individual with osteosarcoma (classified as benign, Zhang_2015), in an individual with a family history of breast and ovarian cancer (classified as a VUS, Maxwell_2016) and in one family with idiopathic HCM where it segregated with disease in 2/3 individuals (maternal grandmother of the proband carried the variant and was unaffected by HCM, Kaski_2012). Furthermore, detailed evaluation by a dysmorphologist with experience in NS and related disorders revealed no phenotypic features suggestive of these conditions in either the proband or her mother (Kaski_2012). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions and in-fact are supportive of a lack of association with the disease phenotype. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, and no additional evidence supporting a pathogenic outcome since its initial evaluation, the variant was re-classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV001143046 SCV001303543 benign Gingival fibromatosis 1 2017-04-27 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001143047 SCV001303544 uncertain significance Noonan syndrome 4 2017-04-27 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761177 SCV000891093 uncertain significance B-Lymphoblastic Leukemia/Lymphoma with Intrachromosomal Amplification of Chromosome 21 2017-05-23 no assertion criteria provided clinical testing

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