ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.3946C>G (p.His1316Asp)

gnomAD frequency: 0.00013  dbSNP: rs371024396
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159185 SCV000209131 likely benign not provided 2021-01-29 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV000461078 SCV000553265 likely benign RASopathy 2023-12-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001375569 SCV001572456 likely benign not specified 2021-04-05 criteria provided, single submitter clinical testing Variant summary: SOS1 c.3946C>G (p.His1316Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251318 control chromosomes (gnomAD). The observed variant frequency is approximately 3.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome phenotype (3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3946C>G in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have 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, the variant was classified as likely benign.
Ambry Genetics RCV002372039 SCV002624414 uncertain significance Cardiovascular phenotype 2022-09-14 criteria provided, single submitter clinical testing The p.H1316D variant (also known as c.3946C>G), located in coding exon 23 of the SOS1 gene, results from a C to G substitution at nucleotide position 3946. The histidine at codon 1316 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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