Variant: NM_007373.3(SHOC2):c.4A>G (p.Ser2Gly)

CA118524

6821 (ClinVar)

Gene: SHOC2

Condition: Noonan syndrome-like disorder with loose anagen hair 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 39b0e509-abdb-415d-87bd-98b7310bb1c0

Approved on: 2017-04-03

Published on: 2018-12-10

HGVS expressions

NM_007373.3:c.4A>G
NM_007373.3(SHOC2):c.4A>G (p.Ser2Gly)
NC_000010.11:g.110964362A>G
CM000672.2:g.110964362A>G
NC_000010.10:g.112724120A>G
CM000672.1:g.112724120A>G
NC_000010.9:g.112714110A>G
NG_028922.1:g.49820A>G
NM_001269039.1:c.4A>G
NM_001269039.2:c.4A>G
NM_001324336.1:c.4A>G
NM_001324337.1:c.4A>G
NR_136749.1:n.116-21266A>G
ENST00000265277.9:c.4A>G
ENST00000369452.8:c.4A>G
ENST00000480155.1:n.488A>G
ENST00000489390.1:n.56-36053A>G
ENST00000489783.1:n.382A>G

Pathogenic

• Met criteria codes: PS2_Very Strong PS3 PS4 PM2 PP2

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.4A>G (p.Ser2Gly) variant in SHOC2 has been reported as a confirmed de novo occurrence in multiple patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; ClinVar SCV000062456.5, SCV000209051.10, SCV000263045.1 PMID 19684605, 21548061, 23918763, 22528146). The p.Ser2Gly variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data GTR ID's: 506381, 28338; PMID: 25563136, 24458587). In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SHOC2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS3, PS4, PM2, PP2.

Met criteria codes

• PS2_Very Strong: The c.4A>G (p.Ser2Gly) variant in SHOC2 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; ClinVar SCV000062456.5, SCV000209051.10, SCV000263045.1 PMID 19684605, 21548061, 23918763, 22528146).
• PS3: In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605).
• PS4: The p.Ser2Gly variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data GTR ID's: 506381, 28338; PMID: 25563136, 24458587)
• PM2: 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