Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_007373.3(SHOC2):c.610A>G (p.Ile204Val)

CA5689600

240838 (ClinVar)

Gene: SHOC2

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: bb194ef7-82a6-4738-913d-0bdd60ad44a4

HGVS expressions

NM_007373.3:c.610A>G

NM_007373.3(SHOC2):c.610A>G (p.Ile204Val)

NC_000010.11:g.110964968A>G

CM000672.2:g.110964968A>G

NC_000010.10:g.112724726A>G

CM000672.1:g.112724726A>G

NC_000010.9:g.112714716A>G

NG_028922.1:g.50426A>G

NM_001269039.1:c.610A>G

NM_001269039.2:c.610A>G

NM_001324336.1:c.610A>G

NM_001324337.1:c.610A>G

NR_136749.1:n.116-20660A>G

ENST00000265277.9:c.610A>G

ENST00000369452.8:c.610A>G

ENST00000451838.1:n.118A>G

ENST00000489390.1:n.56-35447A>G

Benign

BS4 BS2 BP4

BA1 BS1 PS4 PP2 PP1 PM1

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.610A>G (p.Ile204Val) variant in SHOC2 is present in 0.01241% (16/128978) of non-Finnish European alleles in gnomAD. This variant was observed in 3 unaffected individuals as well as several individuals with varying clinical presentations lacking clear associations with a RASopathy (BS2; Invitae internal data, SCV000289856.3; Institut Universitaire d'Hématologie internal data). It was absent from the symptomatic sister of 1 proband with Noonan syndrome who carried this variant (BS4; Institut Universitaire d'Hématologie internal data). Computational analysis and splice site predictors suggest that this variant does not impact the protein (BP4). In summary, the p.Ile204Val variant meets criteria to be classified as benign for autosomal dominant RASopathy. RASopathy-specific ACMG/AMP Criteria applied (PMID:29493581): BS2, BS4, BP4.

BS4

Internal data from Institut Universitaire d'Hématologie: In 1 case with NS, variant was absent from the proband's symptomatic sister. In another case with NS, the variant was inherited from the proband's unaffected father.

BS2

Invitae internal data (SCV000289856.3): observed in 1 juvenile unaffected female. Also observed by Institut Universitaire d'Hématologie in the unaffected sibling of 1 NS proband and the unaffected father of another NS proband.

BP4

REVEL score 0.137. Alamut predicts no impact to splicing. However, UCSC database indicates this codon is conserved - only 1 animal (alligator) has a change to V at this site.

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

Present in 0.01241% (16/128978) of non-Finnish European alleles in gnomADv3; present in 0.0139% (9/64578) of non-Finnish European chromosomes in v3.

PS4

GeneDx internal data (SCV000574438.4): Seen in 1 patient diagnosed with Noonan syndrome, but no phenotype info or info on whether or not other variants were present was available. 2 probands from Institut Universitaire d'Hématologie, but both of these families have unaffected individuals with the variant.

PP2

Not applied due to conflict with BP4.

PP1

Only 1 segregation in 1 family, and this family also had an affected individual without this variant (Institut Universitaire d'Hématologie internal data).

PM1

No PM1 region specified by RAS VCEP.

Approved on: 2020-01-13

Published on: 2020-01-13

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