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.1655G>A (p.Arg552Lys)
- Curation Version - 1.0
- Curation History
- JSON LD for Version 1.0
CA261726
40683 (ClinVar)
Gene: SOS1
Condition: Noonan syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 1065305a-be0c-4399-99c0-352adbd087b7
Approved on: 2019-05-10
Published on: 2019-06-28
HGVS expressions
NM_005633.3:c.1655G>A
NM_005633.3(SOS1):c.1655G>A (p.Arg552Lys)
NC_000002.12:g.39022773C>T
CM000664.2:g.39022773C>T
NC_000002.11:g.39249914C>T
CM000664.1:g.39249914C>T
NC_000002.10:g.39103418C>T
NG_007530.1:g.102691G>A
ENST00000395038.6:c.1655G>A
ENST00000402219.6:c.1655G>A
ENST00000426016.5:c.1655G>A
More
Pathogenic
Met criteria codes 7
PS2_Very Strong
PM1_Strong
PM2
PS4
PS3
PP2
PP3
Not Met criteria codes 16
BA1
PM4
PM5
PM6
BS2
BS1
BS3
BS4
BP1
BP4
BP2
BP3
BP5
BP7
PS1
PP1
Evidence Links 11
Expert Panel
Evidence submitted by expert panel
RASopathy VCEP
The c.1655G>A (p.Arg552Lys) 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 17586837, 17143282, 30266093, 26686981). This variant has been detected in at least 7 independent occurrences with clinical features of a RASopathy (PS4; PMIDs: 17586837, 22420426, 28378436, 29037749, 25337068, 21387466, 21784453, 26918529, 21274610). In vitro functional studies provide some evidence that the p.Arg552Lys variant may impact protein function (PS3; PMID: 21784453). This residue has been defined as a PM1 hotspot by the RAS VCEP. 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). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg552Lys 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, PS3, PM1_Strong, PM2, PP2, PP3.
Met criteria codes
PS2_Very Strong
Patient 133-PRE is a prenatal patient with an AD/de novo heterozygous variant. The phenotypic information for this fetus was not recorded and therefore the clinical suspicion for NS cannot be used for PS4 or PM6/PS2
PubMed:30266093
The p.Arg552Lys variant was identified in a patient with Noonan syndrome with PVS + coronary dilatation and the variant was "further validated by Sanger sequencing using standard protocols and the analysis of proband's parents determined its de novo origin".
PubMed:26686981
PM1_Strong
This residue has been defined as a PM1 hotspot by the RAS VCEP. 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.
PM2
This variant is absent from gnomAD.
PS4
Kilinc et al. 2014: Variant was detected 12 year old boy with tooth anomalies, low set ears, bilateral proptosis, sparse eyebrows, epicanthal folds, hypertelorism, downslanting palpebral fissures, depressed nasal bridge, webbed neck, low posterior hairline, pectus excavatum, cubitus valgus, non palpable left testicle, myopia, scoliosis, diagnossi considered NS.
Partners LMM: The variant has been identified in 6 affected patients with NS at this lab. Inheritance is unknown for these individuals.
GeneDx:
The p.Arg552Lys variant was identified in 1 of the 19 participants in this study with NS. The patient also has hyperopic astigmatism, V pattern in esotropia.
PubMed:28378436
YUWAND melanoma sample...3 variants were identified in the sample p.Phe694_Trp696del, PTPN11 p.Tyr279Cys, and SOS1 p.Arg552Lys
PubMed:26214590
Variant was described to be a causative variant of melanoma and NS. No case evidence provided.
PubMed:27236105
Sequenced 59 patients with NS, 17 with CFC, 5 with Costello, and 2 with NSML and identified the variant in 1 patient with NS. No detailed phenotypic information available.
PubMed:21784453
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. The variant was identified in 2 sporadic cases with NS and 2 "fam.unknown" cases in this study.
PubMed:21387466
The p.Arg552Lys variant was identified in 2 patients with NS/clincially related disorder. Detailed phenotypic information is not available
PubMed:29037749
From March 2006 to March 2011, a total number of 62 patients from southern Tunisia attended the Department of Histology, Faculty of Medicine at the University of Sfax, for genetic counseling and chromosomal and/or molecular analysis for congenital PVS associated with or without another cardiac defect. All patients were ascertained through the Department of Cardiology, Hedi Chaker University Hospital of Sfax. The variant was identified in 8 year old female with NS, PVS, short stature, motor and speech delay, facial dysmorphisms
PubMed:25337068
Variant was identified in an 8 year old female patient with NS
PubMed:21274610
Patient 133-PRE is a prenatal patient with an AD/de novo heterozygous variant. The phenotypic information for this fetus was not recorded and therefore the clinical suspicion for NS cannot be used for PS4 or PM6/PS2
PubMed:30266093
2 newborn patients: Patient 35 and 36 one with cystic hygroma and increased NT and one with hydrops and pyelectasis with clinical suspicions of NS were identified with Tartaglia 2007 as references for pathogenicity of the variant.
PubMed:26918529
PS3
Variant has shown signfiicant increase in ERK activation
PP2
Variant is in SOS1
PP3
REVEL score is 0.837
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
Would be met but PS2_VS is applied so cannot be applied.
Patient 133-PRE is a prenatal patient with an AD/de novo heterozygous variant. The phenotypic information for this fetus was not recorded and therefore the clinical suspicion for NS cannot be used for PS4 or PM6/PS2
PubMed:30266093
The p.Arg552Lys variant was identified in a patient with Noonan syndrome with PVS + coronary dilatation and the variant was "further validated by Sanger sequencing using standard protocols and the analysis of proband's parents determined its de novo origin".
PubMed:26686981
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
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
BP2
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
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
One segregation was identified in Zenker et al. 2007 PMID: 17586837
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.