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.1645A>G (p.Thr549Ala)

CA346365698

561935 (ClinVar)

Gene: SOS1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
UUID: 421d6e49-e013-40c6-b4d6-29c628949bf1

HGVS expressions

NM_005633.3:c.1645A>G
NM_005633.3(SOS1):c.1645A>G (p.Thr549Ala)
NC_000002.12:g.39022783T>C
CM000664.2:g.39022783T>C
NC_000002.11:g.39249924T>C
CM000664.1:g.39249924T>C
NC_000002.10:g.39103428T>C
NG_007530.1:g.102681A>G
ENST00000395038.6:c.1645A>G
ENST00000402219.6:c.1645A>G
ENST00000426016.5:c.1645A>G

Uncertain Significance

Met criteria codes 2
PP2 PM2
Not Met criteria codes 4
PS4 PP3 PM1 PM5

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.1645A>G (p.Thr549Ala) 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
Absent from both versions of gnomAD.
Not Met criteria codes
PS4
Seen in 1 proband at GeneDx without a diagnosis of a RASopathy.
PP3
REVEL score 0.589. 1 animal in the UCSC database (coelacanth) has A at this site; all others have T. Splicing is not predicted to be impacted.
PM1
Does not fall between aa 420-500.
PM5
Only 1 other variant in this codon in ClinVar (c.1646C>A (p.Thr549Lys), VUS as classified by EP).
Approved on: 2020-03-19
Published on: 2020-03-23
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.