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.1654A>T (p.Arg552Trp)

CA16042455

372656 (ClinVar)

Gene: SOS1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: b80c62b7-b2c8-4d2d-97fd-f9770a74e570
Approved on: 2019-05-10
Published on: 2019-06-28

HGVS expressions

NM_005633.3:c.1654A>T
NM_005633.3(SOS1):c.1654A>T (p.Arg552Trp)
ENST00000395038.6:c.1654A>T
ENST00000402219.6:c.1654A>T
ENST00000426016.5:c.1654A>T
NC_000002.12:g.39022774T>A
CM000664.2:g.39022774T>A
NC_000002.11:g.39249915T>A
CM000664.1:g.39249915T>A
NC_000002.10:g.39103419T>A
NG_007530.1:g.102690A>T
More

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 5
PM1_Strong PS4_Supporting PP2 PP3 PM2
Not Met criteria codes 18
BS2 BS1 BS4 BS3 BP5 BP7 BP1 BP4 BP2 BP3 PS3 PS1 PS2 PP1 BA1 PM6 PM4 PM5

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.1654A>T (p.Arg552Trp) variant has been identified in 1 patient with clinical features of a RASopathy (PS4_Supporting; PMID: 22465605). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Of note this p.Arg552 residue is defined as a hotspot by the RAS VCEP. This variant would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore the PM1 rule has been upgraded with expert judgement (PM1_Strong). Computational prediction tools and conservation analysis suggest that the p.Arg552Trp 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): PS4_Supporting, PM2, PM1_Strong, PP2, PP3.
Met criteria codes
PM1_Strong
p.Arg552 residue is defined as a hotspot. 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.
PS4_Supporting
Collazo et al. 2012: Patient with NS with pulmonary stenosis, facial dysmorphism, and cryptochordism with a father with the variant and bilateral cryptochordism, normal stature and NS. Same patient as Ezquieta et al. 2012? Count as one case.
Patient with NS with pulmonary stenosis, facial dysmorphism, and cryptochordism with a father with the variant and bilateral cryptochordism, normal stature and NS PubMed:22465605
PP2
SOS1 is a PP2 gene
PP3
Variant has REVEL score of 0.816
PM2
Variant is absent from gnomAD
Not Met criteria codes
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
BS4
Same patient as described in Collazo et al. 2012 Variant segregated from father with NS to index patient PubMed:22465605
BS3
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
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
PS3
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
Collazo et al. 2012 Variant segregated from father with NS to index patient
Same patient as described in Collazo et al. 2012 Variant segregated from father with NS to index patient PubMed:22465605
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
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.
Curation History
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