Variant: NM_005633.3(SOS1):c.3600C>G (p.Asp1200Glu)

CA297240

40733 (ClinVar)

Gene: SOS1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 9b08e55f-32bb-4cc3-bfff-815c445525b7

HGVS expressions

NM_005633.3:c.3600C>G
NM_005633.3(SOS1):c.3600C>G (p.Asp1200Glu)
NC_000002.12:g.38986226G>C
CM000664.2:g.38986226G>C
NC_000002.11:g.39213367G>C
CM000664.1:g.39213367G>C
NC_000002.10:g.39066871G>C
NG_007530.1:g.139238C>G
ENST00000395038.6:c.3555C>G
ENST00000402219.6:c.3600C>G
ENST00000426016.5:c.3600C>G
ENST00000469581.1:n.343C>G

Likely Benign

• Met criteria codes: BS1 BP4 BP5

• Not Met criteria codes: BA1 BS2 BS4 BS3 BP1 BP2 BP3 BP7 PS4 PS3 PS2 PS1 PP2 PP3 PP1 PM1 PM4 PM5 PM2 PM6

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.3600C>G (p.Asp1200Glu) variant in the SOS1 gene has been identified in at least 6 individuals without detailed phenotypic information as well as one patient with an alternative molecular basis for disease in the BRAF gene (BP5; EGL, Invitae, GeneDx internal data, GTR Lab ID: 500060, 500031, 26957; SCV000854873.1, SCV000553268.3, SCV000209087.11). The filtering allele frequency of the c.3600C>G (p.Asp1200Glu) variant is 0.025% for European (non-Finnish) exomes by the gnomAD database (40/251300 with 95% CI) which is strong evidence to suggest that the variant may be benign based on thresholds defined by the ClinGen RASopathy Expert Panel for autosomal dominant RASopathy variants (BS1). Of note, the c.3600C>A change that also results in p.Asp1200Glu has been identified in one patient with a RASopathy but this variant has not met criteria to be classified as pathogenic and therefore PM5 is not met (Partners LMM internal data; GTR Lab ID: 21766; SCV000062231.5). Computational prediction tools and conservation analysis suggest that the p.Asp1200Glu variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP4, BP5.

Met criteria codes

• BS1: This variant has been observed in 42/126584 (0.00033)
• BP4: REVEL score of 0.207 which is low and only mutation taster is predicting Path. There are several mammals including the chinchilla and the horse.
• BP5: GeneDx: seen in patient with p.Gly596Val in BRAF

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS2: 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
• 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
• 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
• PS4: EGL: Found varint in het state from 2 short stature panels but neither case had detailed clinical information to molecularly diagnose the patient with a RASopathy. Invitae: We saw 3600C>G in 3 juvenile patients without a provided phenotype and one adult without a provided phenotype,
• PS3: 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
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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
• PM1: 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
• PM5: 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

Approved on: 2019-06-27

Published on: 2019-06-28