Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

Variant: NM_005633.3(SOS1):c.1656G>C (p.Arg552Ser)

CA256580

12872 (ClinVar)

Gene: SOS1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 7b69757f-5512-4640-93f6-c926e38cf7f9
Approved on: 2019-05-10
Published on: 2019-06-28

HGVS expressions

NM_005633.3:c.1656G>C
NM_005633.3(SOS1):c.1656G>C (p.Arg552Ser)
NC_000002.12:g.39022772C>G
CM000664.2:g.39022772C>G
NC_000002.11:g.39249913C>G
CM000664.1:g.39249913C>G
NC_000002.10:g.39103417C>G
NG_007530.1:g.102692G>C
ENST00000395038.6:c.1656G>C
ENST00000402219.6:c.1656G>C
ENST00000426016.5:c.1656G>C
More

Pathogenic

Met criteria codes 7
PS3 PS4 PP2 PP3 PM2 PS2_Very Strong PM1_Strong
Not Met criteria codes 16
PS1 BP2 BP1 BP4 BP3 BP5 BP7 BA1 PP1 PM4 PM5 PM6 BS2 BS1 BS3 BS4

Evidence Links 16

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.1656G>C (p.Arg552Ser) variant in SOS1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 17143282). This variant has also been identified in at least 7 independent occurrences in patients with clinical features of a RASopathy (PS4; PMIDs: 26297936, 25862627, 17143282, 21387466, 19020799, 23885229, 22190897, 19352411). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Arg552Ser variant may impact protein function (PS3; PMID: 27304678). This residue has been identified as a hot spot. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been upgraded with expert judgement (PM1_Strong). Computational prediction tools and conservation analysis suggest that the p.Arg552Ser variant may impact the protein (PP3). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4, PM2, PS3, PM1_Strong, PP2, PP3.
Met criteria codes
PS3
variant increased p-ERK signaling (PMID 27304678)
Transfected wild-type and mutant SOS1 constructs into HEK293T cells and measured the effect on basal levels of phosphorylated ERK1/2. Found that the p.R552S variant significantly increased p-ERK signaling relative to WT (p = 0.0039). This meets criteria for PS3. PubMed:27304678
PS4
This variant was reported in at least 7 patients with clinical features of NS (PMID: 26297936, 25862627, 17143282, 21387466, 19020799, 23885229, 22190897, 19352411)
Four cohorts were included in this study...143 clinically well-characterized patients with NS of European/Italian ancestry, patients from the Sarkozy 2009 study, (N= 358) anonymous samples from individuals with phenotypes suggestive of NS from commercial DNA diagnostic testing, finally a cohort of 59 subjects with nonsyndromic CHD's. This was a large study of patients with clinical features of a RASopathy that has been described elsewhere. This study describes c.1656G>C (p.Arg552Ser) in 2 sporadic, 7 fam unknown cases PubMed:21387466
This case report of a 14 year old girl with chronic pain in NS identified the p.Arg552Ser variant. The c.DNA change was not reported. PubMed:26297936
The p.Arg552Ser variant was identified in this NS patient with pigmented villonodular synovitis. The c.DNA change is not described in this case study. Therefore this occurrence cannot be counted. PubMed:18925667
Sequenced 97 Noonan syndrome patients and identified the p.Arg552Ser in one patient who did not have hearing loss in this NS/HL cohort. PubMed:25862627
59 patients with NS, 17 with cardiofaciocutaneous syndrome, 5 with Costello syndrome, and 2 with LEOPARD syndrome were sequenced and 2 of the patients had p.Arg552Ser variants. These are likely the Korean patients described in the Ko paper as these patients are also from Korea. PubMed:21784453
This study sequenced 42 patients from the Outpatient Clinic of the Genetics Unit of the Children's Hospital and reported 2 patients with the p.Arg552Ser variants. The cohort is considered a NS, NSML and CFC cohort, but detailed phenotypic information and c.DNA change is not provided. Cannot count. PubMed:22488759
This study sequenced 96/134 patients with clinical features fitting the RASopathy spectrum evaluated in their first year of life.This variant was identified in one patient with NS. PubMed:22190897
2 patients with variant. Patient 1: Stenosis of the pulmonary valve, diagnosed in early infancy, typical features of NS. Karyotype was 46, XY, inv(9) (p11q13). Bilateral radiolucent cysts of the mandible, normal stature and no learning difficulties. Patient had the p.Arg552Ser variant. Patient 3: Stenosis of the pulmonary artery and atrial septal defect. Clinical features typical for NS. PVS of the left ankle diagnosed at 12 years, delaryed puberty, left cryptorchidism, no learning disabilities. No involvement of the jaws. The p.Arg552Ser variant was present in this individual with unknown inheritance. PubMed:19352411
This study sequenced 19 patients with NS and the p.Arg552Ser varinat was identified in Patient 18. There was no indication of which c.DNA change was identified in this patient. PubMed:28378436
Of the 59 Korean NS patients sequenced, 2 of the patients in this study had the c.1656G>C p.R552S variants. PubMed:19020799
Identified the p.Arg552Ser variant in a patient with NS but no additional clinical information is available. It is not stated which c. change this is. Additionally it is unclear how many patients were identified with this variant. PubMed:22465605
The p.Arg552Ser variant was identified in 2 de novo occurrences in patients with Noonan syndrome. Variants were absent from both parents and paternity was confirmed for each. PubMed:17143282
In this paper, cancer samples were sequenced and they identified the p.Arg552Ser variant. They identified both the c.1656G>C and c.1656G>T variant, each in 1 occurrence. PubMed:29625050
Case 4, an 82 year old man with late-onset HCM was found to carry the pathogenic c.1656G>C (p.Arg552Ser). The allelic fraction for the variant was 24% via NGS suggestive of mosaicism. Sanger sequencing was consistent. This mosaicism is likely the reason for the nonsyndromic HCM presentation. PubMed:29696744
Sequenced 33 NS patients and Identified the c.1656G>C (p.Arg552Ser) variant in one patient. The variant was inherited from an affected mother. The patient was a female with typical face, hypertelorism, downslanting palpebral fissures , ptosis, curly hair, sparse eyebrows, webbed/short neck, pectus deformity, keratosis, Navl/lentigines, short stature, easy bruising, heart defect, pulmonary stenosis, aberrant ECG, left-axis deviation PubMed:23885229
PP2
SOS1 gene meets PP2
PP3
REVEL score 0.863
PM2
Variant is absent from gnomAD
PS2_Very Strong
The p.Arg552Ser variant was identified in 2 de novo occurrences in patients with Noonan syndrome. Variants were absent from both parents and paternity was confirmed for each.
The p.Arg552Ser variant was identified in 2 de novo occurrences in patients with Noonan syndrome. Variants were absent from both parents and paternity was confirmed for each. PubMed:17143282
PM1_Strong
This residue has been identified as a hot spot. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been upgraded with expert judgement.
Not Met criteria codes
PS1
This variant will be used to support the pathogenicity of the c.1656G>T transition in SOS1
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
Variant segregated in one mother child duo (PMID: 23885229).
Sequenced 33 NS patients and Identified the c.1656G>C (p.Arg552Ser) variant in one patient. The variant was inherited from an affected mother. The patient was a female with typical face, hypertelorism, downslanting palpebral fissures , ptosis, curly hair, sparse eyebrows, webbed/short neck, pectus deformity, keratosis, Navl/lentigines, short stature, easy bruising, heart defect, pulmonary stenosis, aberrant ECG, left-axis deviation PubMed:23885229
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
There are multiple pathogenic variants at this codon. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been removed
PM6
PM6 cannot be applied because PS2_VS has been applied.
The p.Arg552Ser variant was identified in 2 de novo occurrences in patients with Noonan syndrome. Variants were absent from both parents and paternity was confirmed for each. PubMed:17143282
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
Sequenced 33 NS patients and Identified the c.1656G>C (p.Arg552Ser) variant in one patient. The variant was inherited from an affected mother. The patient was a female with typical face, hypertelorism, downslanting palpebral fissures , ptosis, curly hair, sparse eyebrows, webbed/short neck, pectus deformity, keratosis, Navl/lentigines, short stature, easy bruising, heart defect, pulmonary stenosis, aberrant ECG, left-axis deviation PubMed:23885229
Curation History
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