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]
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  • See Evidence submitted by expert panel for details.

Variant: NM_005633.3(SOS1):c.512T>G (p.Val171Gly)

CA136165

40654 (ClinVar)

Gene: SOS1
Condition: Noonan syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 2006faae-1689-4eab-b2b4-ad0ca1e3a543
Approved on: 2019-02-28
Published on: 2020-03-12

HGVS expressions

NM_005633.3:c.512T>G
NM_005633.3(SOS1):c.512T>G (p.Val171Gly)
NC_000002.12:g.39054822A>C
CM000664.2:g.39054822A>C
NC_000002.11:g.39281963A>C
CM000664.1:g.39281963A>C
NC_000002.10:g.39135467A>C
NG_007530.1:g.70642T>G
ENST00000395038.6:c.512T>G
ENST00000402219.6:c.512T>G
ENST00000426016.5:c.512T>G

Pathogenic

Met criteria codes 5
PS4_Moderate PS2 PM2 PP3 PP2
Not Met criteria codes 18
BS2 BS1 BS4 BS3 BP4 BP1 BP2 BP3 BP5 BP7 PS1 PS3 PM5 PM4 PM1 BA1 PM6 PP1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.512T>G (p.Val171Gly) variant has been identified in a patient with clinical features of a RASopathy in a de novo occurance (PS2; Ambry Genetics internal data, GTR ID: 61756, ClinVar SCV000742607.1) This variant has also been identified in two other independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate PMID: 26918529, Partners LMM, Invitae internal data; GTR ID: 21766, 500031 ClinVar SCV000062241.5, SCV000553263.2). Of note, a different likely pathogenic missense variant (p.Val171Ala) has been previously identified at this codon of SOS1 (PM5 not met; ClinVar 45373). The p.Val171Gly variant in the SOS1 gene was absent from gnomAD (PM2). Computational prediction tools and conservation analysis suggest that the p.Val171Gly variant may impact the protein (PP3). Of note, the variant occurs at the second nucleotide of exon 5 (in-frame) but no functional evidence has indicated that the variant would cause skipping of the exon. 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, PS4_Moderate, PM2, PP3, PP2.
Met criteria codes
PS4_Moderate
The Val171Gly variant in SOS1 has been previously identified in one individual with clinical features of Noonan syndrome (LMM published data Hakami 2016). The variant was also reported in a patient with features of a RASopathy in a de novo case from Ambry genetics. Invitae data form John Garcia: juvenile female who was tested with the RASopathies Comprehensive Panel. This was the only reportable variant. The patient was said to have a history and appearance consistent with Noonan/CFC, with multiple giant cell lesions on mandible, maxilla and other joints. Unfortunately, we have not tested the parents or any other family members so we don't have any additional segregation or de novo data If we count this as PS4_Moderate due to 3 independent occurrences this will reach Pathogenic and the p.Val171Ala will be impacted.
SOS1 c.512 T>G p.Val171Gly variant was identified in Newborn 9 (Noonan syndrome) in Hakami et al. 2016 who had a congenital heart defect. the paper classified this variant as VUS- favor pathogenic. PubMed:26918529
PS2
This was identified in an 11 year old girl who was small for her age and had a clinical diagnosis of Noonan syndrome, multi-focal giant cell granulomas, history of pulmonary stenosis, pulmonary lymphectasia, chronic lymphedema, coagulopathy, developmental delay, and dysmorphic features. Multi-gene panel testing for Noonan syndrome identified a variant of uncertain significance in SOS1. She had exome testing and the SOS1 c.512T>C variant was found to be confirmed in de novo trio. (Ambry Genetics internal data)
PM2
The p.Val171Gly variant in the SOS1 gene was absent from gnomAD (PM2).
PP3
REVEL score of 0.735, need to ask the RAS group what we will use for the REVEL cutoff.
PP2
The SOS1 gene has variants in the original RASopathy set of genes with PP2 applied.
Not Met criteria codes
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
The p.Val171Gly variant in the SOS1 gene was absent from gnomAD (PM2).
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
BP4
REVEL score of 0.735, need to ask the RAS group what we will use for the REVEL cutoff.
BP1
The SOS1 gene has variants in the original RASopathy set of genes with PP2 applied.
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
Not applying because LMM data (where all this data is from) indicates that the patient with the p.Val171Gly variant only has that variant despite classifying it as a VUS.
This paper has newborns numbered 1-9 in table 2 and it is unclear as to whether they match up with Table 1's probands. Newborn 9 has the variant in question (Table 2) but newborn 9 in Table 1 has a PTPN11 p.Phe71Leu. Not applying because LMM data (where all this data is from) indicates that the patient with the p.Val171Gly variant only has that variant despite classifying it as a VUS. PubMed:26918529
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
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
In addition, another variant (Val171Ala) at the same codon was identified as a de novo variant in one proband with clinical features of Noonan syndrome (LMM unpublished data) suggesting that changes at this position may not be tolerated. This variant was classified as Likely Pathogenic. The p.Val171Ala variant was identified in a de novo occurance in one proband with clinical features of NS at the LMM. Variant was classified as LP by LMM Has also been identified in 1 patient w/possible familial RASopathy in Leung et al. 2018 PMID:29402968 Variant would only meet PM6 and PM2
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
RAS EP does not specify that this is the functional domain
BA1
The p.Val171Gly variant in the SOS1 gene was absent from gnomAD (PM2).
PM6
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
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