10-110964877-G-A

Variant names:

• chr10-110964877-G-A
• rs730881020
• NM_007373.4:c.519G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS4 PS2 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.519G>A variant in the SHOC2 gene is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 173 (p.Met173Ile). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.768 (PP3). This variant has been identified as a de novo occurrence with confirmed parental relationships in 3 individuals and with unconfirmed parental relationships in 1 individual with RASopathy (PS2_VeryStrong; Invitae, GeneDx, Ambry, Genomic Medicine Lab; ClinVar SCV001573982.4, SCV000209055.14, SCV002641556.1, SCV001573024.1). This variant has been reported in more than 5 probands diagnosed with RASopathy (PS4; PMIDs: 25137548, 29907801; Invitae, GeneDx, UCSF Genomic Medicine Lab, LabCorp, Ambry; ClinVar SCV001573982.4, SCV000209055.14, SCV001573024.1, SCV000699327.2, SCV002641556.1). ERK phosphorylation assays showed that this variant decreases the ability of SHOC2 to accelerate ERK1/2 phosphorylation (PS3 not met, PMID:25137548). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PM2_Supporting, PP3 (Specification Version 2.1, 09/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA199174/MONDO:0021060/038

• Frequency: Genomes: not found (cov: 32)
• Consequence: SHOC2 NM_007373.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9 U:1
• Conservation: PhyloP100: 10.0
• Publications: 11 publications found

Genes affected

SHOC2 (HGNC:15454): (SHOC2 leucine rich repeat scaffold protein) This gene encodes a protein that consists almost entirely of leucine-rich repeats, a domain implicated in protein-protein interactions. The protein may function as a scaffold linking RAS to downstream signal transducers in the RAS/ERK MAP kinase signaling cascade. Mutations in this gene have been associated with Noonan-like syndrome with loose anagen hair. [provided by RefSeq, May 2010]

SHOC2 Gene-Disease associations (from GenCC):

• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome-like disorder with loose anagen hair 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, PanelApp Australia
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007373.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOC2	NM_007373.4	MANE Select	c.519G>A	p.Met173Ile	missense	Exon 2 of 9	NP_031399.2
	SHOC2	NM_001324336.2		c.519G>A	p.Met173Ile	missense	Exon 2 of 9	NP_001311265.1	Q9UQ13-1
	SHOC2	NM_001324337.2		c.519G>A	p.Met173Ile	missense	Exon 3 of 10	NP_001311266.1	Q9UQ13-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHOC2	ENST00000369452.9	TSL:1 MANE Select	c.519G>A	p.Met173Ile	missense	Exon 2 of 9	ENSP00000358464.5	Q9UQ13-1
	SHOC2	ENST00000685059.1		c.519G>A	p.Met173Ile	missense	Exon 3 of 10	ENSP00000510210.1	Q9UQ13-1
	SHOC2	ENST00000688928.1		c.519G>A	p.Met173Ile	missense	Exon 2 of 9	ENSP00000509273.1	Q9UQ13-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000534 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Noonan syndrome-like disorder with loose anagen hair 1 (3)
2	-	-	RASopathy (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Non-immune hydrops fetalis (1)
1	-	-	not provided (1)
-	1	-	not specified (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.0022	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.12	N
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.27	N
REVEL	Pathogenic	0.77
Sift	Benign	0.075	T
Sift4G	Benign	0.24	T
Polyphen		0.0040	B
Vest4		0.80
MutPred		0.32		Loss of catalytic residue at M173 (P = 0.0094)
MVP		0.45
MPC		0.56
ClinPred		0.84	D
GERP RS		4.9
Varity_R		0.21
gMVP		0.58
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730881020; hg19: chr10-112724635;