ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.643T>C (p.Tyr215His)

gnomAD frequency: 0.00001  dbSNP: rs730881039
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000704276 SCV001192870 uncertain significance RASopathy 2019-09-24 reviewed by expert panel curation The c.643T>C (p.Tyr215His) variant in the SOS1 gene is present in 0.014% (5/35434) Latino alleles in gnomAD (BS1 not met). This variant was observed in 9 healthy adult individuals who did not have clinical features of a RASopathy (BS2; SCV000209098.13). In summary, the clinical significance of the p.Tyr215His variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS2.
GeneDx RCV000159154 SCV000209098 likely benign not provided 2019-03-04 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000704276 SCV000833218 uncertain significance RASopathy 2023-12-19 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 215 of the SOS1 protein (p.Tyr215His). This variant is present in population databases (rs730881039, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 181547). 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 SOS1 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.
Illumina Laboratory Services, Illumina RCV001141421 SCV001301765 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV001141422 SCV001301766 uncertain significance Fibromatosis, gingival, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Fulgent Genetics, Fulgent Genetics RCV002505192 SCV002815457 uncertain significance Fibromatosis, gingival, 1; Noonan syndrome 4 2021-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV004019926 SCV003741407 uncertain significance Cardiovascular phenotype 2023-02-08 criteria provided, single submitter clinical testing The p.Y215H variant (also known as c.643T>C), located in coding exon 5 of the SOS1 gene, results from a T to C substitution at nucleotide position 643. The tyrosine at codon 215 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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