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.1018C>T (p.Pro340Ser)

CA1624660

40664 (ClinVar)

Gene: SOS1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: dc725e41-14fe-44e9-9d51-91ac14a1c2d3
Approved on: 2019-06-27
Published on: 2019-06-28

HGVS expressions

NM_005633.3:c.1018C>T
NM_005633.3(SOS1):c.1018C>T (p.Pro340Ser)
NC_000002.12:g.39035268G>A
CM000664.2:g.39035268G>A
NC_000002.11:g.39262409G>A
CM000664.1:g.39262409G>A
NC_000002.10:g.39115913G>A
NG_007530.1:g.90196C>T
ENST00000395038.6:c.1018C>T
ENST00000402219.6:c.1018C>T
ENST00000426016.5:c.1018C>T
ENST00000461545.1:n.368C>T
More

Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"
Met criteria codes 4
PP2 BS1 BS4 BP5
Not Met criteria codes 19
PP3 PP1 PM5 PM4 PM1 PM2 PM6 BA1 BS2 BS3 BP1 BP4 BP2 BP3 BP7 PS1 PS2 PS4 PS3

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.1018C>T (p.Pro340Ser) variant in the SOS1 gene has been found not to segregate in a family member of a patient who underwent testing for RASopathies as well as another adult who was unaffected (BS4; GeneDx, Invitae internal data; GTR Lab ID: 26957, 500031; SCV000514724.5, SCV000659124.2). This variant has also been identified in a patient with an alternate molecular basis of disease (BP5; PMID 22585553). The filtering allele frequency of the p.Pro340Ser variant is 0.022% for East Asian exomes in the gnomAD database (20/251276 with 95% CI), which is high enough frequency to be considered strong evidence for the variant being benign by the ClinGen RASopathy Expert Panel (BS1). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4, BP5, BS1.
Met criteria codes
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
This variant was identified in 9/18838 (0.00048) East Asian alleles in gnomAD. This is above the BS1 cutoff but is just below the BA1 cutoff. You could round up to 0.0005 for BA1.
BS4
This variant was identified in an unaffected parent at GeneDx
BP5
Fahrner et al. 2012 (22585553): Proband with clinical features of NSML/NS and a PTPN11 p.Thr468Met path variant as well as the SOS1 variant.
Proband with the variant had clincial features suggestive of a RASopathy, (overlapping features of PTPN11 related NSML and SOS1 related NS) but the patient also carried the PTPN11 p.T468M variant which is an established pathgoenic variant. It is unclear whether we should use BP5 for this case or not. PubMed:22585553
Not Met criteria codes
PP3
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
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
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
BS2
Invitae: Observed in one adult female who was unaffected
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
PS1
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
PS4
Invitae: Observed variants in two unrelated juveniles without provided phenotype
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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.