rs727505093

Positions:

• chr2-39014838-A-C
• chr2-39014838-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_005633.4(SOS1):​c.1867T>G​(p.Phe623Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F623I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 8.92

Genes affected

SOS1 (HGNC:11187): (SOS Ras/Rac guanine nucleotide exchange factor 1) This gene encodes a protein that is a guanine nucleotide exchange factor for RAS proteins, membrane proteins that bind guanine nucleotides and participate in signal transduction pathways. GTP binding activates and GTP hydrolysis inactivates RAS proteins. The product of this gene may regulate RAS proteins by facilitating the exchange of GTP for GDP. Mutations in this gene are associated with gingival fibromatosis 1 and Noonan syndrome type 4. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-39014838-A-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 2-39014838-A-C is Pathogenic according to our data. Variant chr2-39014838-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179739.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4	c.1867T>G	p.Phe623Val	missense_variant	11/23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.1867T>G	p.Phe623Val	missense_variant	11/23	1	NM_005633.4	ENSP00000384675	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2023

Observed in a proband with hypertrophic cardiomyopathy in the published literature (Baban et al., 2019); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29493581, 22589294, 31368652, 17586837, 20673819) -

Noonan syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 26, 2017

The p.Phe623Val variant in SOS1 occurred de novo in 1 individual with clinical f eatures of a RASopathy (LMM data) and has been reported in ClinVar (Variation ID 179739). This variant was absent from large population studies. An additional a mino acid change at this position (p.Phe623Ile) was identified in two probands w ith clinical features of Noonan syndrome, which occured de novo in 1 of these in dividuals with confirmed paternity (Zenker 2007, Fabretto 2010). Computational p rediction tools and conservation analysis do not provide strong support for or a gainst an impact to the protein. In summary, although additional studies are req uired to fully establish its clinical significance, the p.Phe623Val variant is l ikely pathogenic. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 12, 2021

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 26, 2019

Variant summary: SOS1 c.1867T>G (p.Phe623Val) results in a non-conservative amino acid change located in the N-terminal Ras-like guanine nucleotide exchange factor domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function (ACMG PP3). The variant was absent in 276468 control chromosomes (gnomAD) (ACMG PM2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1867T>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. However, a variant at the same codon (p.Phe623Ile) has been reported in individuals in association with Noonan syndrome, including one de novo occurrence (Fabretto_2010, Zenker_2007), suggesting the location to be important for protein function. Substitution of the Phe623 residue by another amino acid has been hypothesized to cause altered guanine nucleotide exchange activity of SOS1 and perturb the catalytic activity of the CDC25 domain (Lepri_2011, Zenker_2007) (ACMG PM5). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as likely pathogenic. One of these assessments mentions a "reportedly" de-novo occurrence of this variant in one individual with clinical features of RASopathy although we do not have independent evidence to corroborate. This variant was identified once in our laboratory in an adult female patient tested on a panel for Noonan syndrome and related disorders. A definitive clinical indication was not provided, the patient is lost to follow-up and no additional testing has been performed. Based on the evidence outlined above, the variant was classified as uncertain significance until additional information (i.e., clinical and functional studies) becomes available. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;D;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Pathogenic	3.6	H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.92
MutPred		0.83		Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);
MVP		0.92
MPC		1.7
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs727505093; hg19: chr2-39241979; COSMIC: COSV105933669;