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.512T>C (p.Val171Ala)

CA261743

45373 (ClinVar)

Gene: SOS1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 6d026472-974f-4b44-9918-65310c34a46d
Approved on: 2019-02-28
Published on: 2019-07-15

HGVS expressions

NM_005633.3:c.512T>C
NM_005633.3(SOS1):c.512T>C (p.Val171Ala)
NC_000002.12:g.39054822A>G
CM000664.2:g.39054822A>G
NC_000002.11:g.39281963A>G
CM000664.1:g.39281963A>G
NC_000002.10:g.39135467A>G
NG_007530.1:g.70642T>C
ENST00000395038.6:c.512T>C
ENST00000402219.6:c.512T>C
ENST00000426016.5:c.512T>C
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Likely Pathogenic

Met criteria codes 5
PS4_Supporting PP2 PM6 PM2 PM5
Not Met criteria codes 18
BS2 BS1 BS3 BS4 BP4 BP1 BP2 BP3 BP5 BP7 PS2 PS3 PS1 BA1 PP3 PP1 PM4 PM1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.512T>C (p.Val171Ala) variant in SOS1 has been reported as an unconfirmed de novo occurrence in a patient with clinical features of a Noonan spectrum disorder (PM6; Partners LMM internal data; GTR Lab ID: 21766; ClinVar SCV000062240.5). The p.Val171Ala variant has also been identified in another independent occurrences in patients with clinical features of a familial RASopathy (PS4_Supporting; PMID: 29402968). This variant was absent from large population studies (PM2; gnomAD, http://gnomAD.broadinstitute.org). A different pathogenic missense variant (p.Val171Gly) has been previously identified at this codon of SOS1 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 40654). 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): PM6, PM5, PM2, PS4_Supporting, PP2.
Met criteria codes
PS4_Supporting
Has also been identified in 1 patient w/possible familial RASopathy in Leung et al. 2018 PMID:29402968
Variant was identified in a patient with a possible familial RASopathy, see supplemental table. PubMed:29402968
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
The p.Val171Ala variant was identified in a de novo occurrence in one proband with clinical features of NS at the LMM.
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
This variant is at the same codon as the p.Val171Gly variant which is classified as Pathogenic.
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
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
BP4
REVEL score = 0.566
BP1
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
PS2
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
REVEL score = 0.566
PP1
In the supplement of Leung 2018 29402968 there is the following statment: "familal case(?Mother (with CoA) and siblings)" however this is not enough information to confirm segregation evidence.
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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