Variant: NM_005633.3(SOS1):c.1646C>A (p.Thr549Lys)

CA297273

181553 (ClinVar)

Gene: SOS1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 2dd0ebb9-58e1-4d39-8701-92f8a938db1a

Approved on: 2020-03-23

Published on: 2020-03-23

HGVS expressions

NM_005633.3:c.1646C>A
NM_005633.3(SOS1):c.1646C>A (p.Thr549Lys)
NC_000002.12:g.39022782G>T
CM000664.2:g.39022782G>T
NC_000002.11:g.39249923G>T
CM000664.1:g.39249923G>T
NC_000002.10:g.39103427G>T
NG_007530.1:g.102682C>A
ENST00000395038.6:c.1646C>A
ENST00000402219.6:c.1646C>A
ENST00000426016.5:c.1646C>A

Uncertain Significance

• Met criteria codes: PP2 PM2

• Not Met criteria codes: BA1 BS1 PP3 PM5 PM1 PS4

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.1646C>A (p.Thr549Lys) variant in SOS1 was absent from large population studies (PM2; gnomad.broadinstitute.org). 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 variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied: PM2, PP2.

Met criteria codes

• PP2: SOS1 is a missense-constrained gene.
• PM2: This variant was absent from both versions of gnomAD.

Not Met criteria codes

• BA1: 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
• PP3: REVEL score 0.685. Conserved in UCSC database except for 1 fish. (Splicing is not predicted to be impacted.)
• PM5: 1 other variant in this codon was classified as a VUS by the EP.
• PM1: Does not fall between aa 420-500.
• PS4: Seen in 3 probands without diagnoses of RASopathies.