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.1655G>T (p.Arg552Met)

CA16616762

40681 (ClinVar)

Gene: SOS1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: b58990d7-5f0e-4d39-bc5c-0202598cfebe
Approved on: 2019-05-10
Published on: 2019-06-28

HGVS expressions

NM_005633.3:c.1655G>T
NM_005633.3(SOS1):c.1655G>T (p.Arg552Met)
ENST00000395038.6:c.1655G>T
ENST00000402219.6:c.1655G>T
ENST00000426016.5:c.1655G>T
NC_000002.12:g.39022773C>A
CM000664.2:g.39022773C>A
NC_000002.11:g.39249914C>A
CM000664.1:g.39249914C>A
NC_000002.10:g.39103418C>A
NG_007530.1:g.102691G>T
More

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 4
PM1_Strong PS4_Moderate PP2 PP3
Not Met criteria codes 19
BS2 BS1 BS4 BS3 BP5 BP7 BP1 BP4 BP2 BP3 PS3 PS1 PS2 PP1 BA1 PM2 PM6 PM4 PM5

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.1655G>T (p.Arg552Met) variant has been identified in at least 3 independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate; GeneDx internal data; GTR Lab IDs 26957; SCV000565586.5 PMID: 21387466). his AA residue has been specified as a hotspot for variation. 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.Arg552Met 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 likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PM1_Strong, PP2, PP3.
Met criteria codes
PM1_Strong
This AA residue has been specified as a hotspot for variation. 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_Moderate
GeneDx- Variant seen in a proband, sibling, and parent all with Noonan syndrome Invitae- observed p.Arg552Met once in patient with clinical features of RASopathy Didn’t do additional family testing Lepri 2011: Patient NS25 is one patient with the p.Arg552Met variant
Patient NS25: 11y 7m old Male with neonatal/infantile growth failure, short stature, delayed bone age, craniofacial anomalies, high forehead bitemporal narrowing, downslanting palpebral fissures and epicanthal folds has p.Arg552Met variant in sporadic case with inheritance unknown. This paper states that there are 2 patients with this variant and clinical features of NS but clinical information for the second patient is not available. PubMed:21387466
Sequenced over 9,000 tumors and identified the p.Arg552Met variant in one sample. PubMed:29625050
PP2
Variant is in BRAF
PP3
REVEL score = 0.903
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
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
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
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
PM2
Variant has been identified in 1/111178 European (Non-Finnish) alleles in gnomAD.
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: when all variants are assessed there should be at least 2 but specify which ones here. 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 and PM1 has been upgraded
Curation History
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