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>T (p.Arg552Ser)

CA261730

40684 (ClinVar)

Gene: SOS1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: b1bb4dae-8f06-4a91-b1c4-ccf1a3d0092f
Approved on: 2019-05-10
Published on: 2019-06-28

HGVS expressions

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

Pathogenic

Met criteria codes 7
PS2 PS1 PM2 PP2 PP3 PM1_Strong PS4_Moderate
Not Met criteria codes 16
BP1 BP4 BP2 BP3 BP7 BP5 PS3 BA1 PM6 PM5 PM4 PP1 BS2 BS1 BS4 BS3

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.1656G>T (p.Arg552Ser) variant in SOS1 has been reported as a confirmed de novo occurrence in one patient and 2 other probands with clinical features of a RASopathy (PS2, PS4_Moderate; PMID 17586837, 18854871). Of note, one of these cases was an affected mother-child duo (PP1 not met; PMID: 17586837). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). This amino acid residue has been designated 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 (PM1_Strong). Of note, the p.Arg552Ser variant in SOS1 has also been a consequence of the c.1656G>C nucleotide change which has been classified as pathogenic (PS1; ClinVar ID 12872). 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, PS1, PM1_Strong, PM2, PS4_Moderate, PP2, PP3.
Met criteria codes
PS2
Variant identified in a confirmed de novo case. The c.1656G>T varinat was identified in 1 sporadic case and 1 familial observation. The familial observation was an affected mother-child duo. The sporadic case was confirmed to be de novo.
The c.1656G>T varinat was identified in 1 sporadic case and 1 familial observation. The familial observation was an affected mother-child duo. The sporadic case was confirmed to be de novo. PubMed:17586837
PS1
The c.1656G>C variant is classified as Pathogenic by the RAS EP.
PM2
this variant is absent from gnomAD.
PP2
SOS1 gene is PP2 gene
PP3
REVEL score 0.863
PM1_Strong
This amino acid residue has been designated 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_Moderate
This variant has been reported in at least 3 occurrences in the literature in patients with a RASopathy (PMID: 17586837, 18854871)
Sequenced 75 index cases with syndromic MGCL and identified the p.Arg552Ser variant in a 28 year old female who was diagnosed with NS with MGCL at age 11. The patien has short stature, PS, ASD, Pectus deformation, webbed neck, curly hair, hearing impairment, ptosis. The inheritance of the variant is not described. PubMed:18854871
The c.1656G>T variant was identified in 1 sporadic case and 1 familial observation. The familial observation was an affected mother-child duo. The sporadic case was confirmed to be de novo. PubMed:17586837
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
Not Met criteria codes
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
BP7
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
PS3
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
PM6
The de novo case was said to be "confirmed" but may downgrade to PM6 if this isn't sufficient for PS2.
The c.1656G>T varinat was identified in 1 sporadic case and 1 familial observation. The familial observation was an affected mother-child duo. The sporadic case was confirmed to be de novo. PubMed:17586837
PM5
There are multiple missense variants at this codon that are pathogenic. 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
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
This variant was in a mother child pair with NS.
The c.1656G>T varinat was identified in 1 sporadic case and 1 familial observation. The familial observation was an affected mother-child duo. The sporadic case was confirmed to be de novo. PubMed:17586837
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
The c.1656G>T varinat was identified in 1 sporadic case and 1 familial observation. The familial observation was an affected mother-child duo. The sporadic case was confirmed to be de novo. PubMed:17586837
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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