Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000471101 | SCV000616424 | uncertain significance | RASopathy | 2017-04-03 | reviewed by expert panel | curation | The c.935T>C p.Val312Ala variant has been identified in 2 probands with clinical features of RASopathies (PS4 not met; GeneDx, Partners LMM internal data; GTR ID's: 26957, 21766; ClinVar SCV000200036.4; SCV000209006.12). Computational prediction tools and conservation analysis suggest that the p.Val312Ala variant does not impact the protein (BP4). In summary, the clinical significance of the p.Val312Ala variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP4. |
Laboratory for Molecular Medicine, |
RCV000151711 | SCV000200036 | uncertain significance | not specified | 2013-12-05 | criteria provided, single submitter | clinical testing | The Val312Ala variant in RAF1 has not been previously reported in other families with clinical features of Noonan spectrum disorders, but has been identified in 1/8600 European American chromosomes by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS). Of note, another variant at this position, Val31 2Gly, has been identified in one fetus with abnormal ultrasound findings and a n ormal karyotype (Croonen 2013). Valine (Val) at position 312 is not conserved in mammals or across evolutionarily distant species, and several mammals and other species (including cow, sheep, antelope, and fish species) have an alanine (Ala ) at this position, suggesting that this change may be tolerated. Other computat ional analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIF T) suggest that the Val312Ala variant may not impact the protein. In summary, ad ditional information is needed to fully assess the clinical significance of the Val312Ala variant. |
Gene |
RCV000680307 | SCV000209006 | likely benign | not provided | 2021-02-01 | criteria provided, single submitter | clinical testing | Observed in a newborn with a suspected Noonan spectrum disorder in published literature (Hakami et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31032133, 27974047, 26918529) |
Ambry Genetics | RCV000246938 | SCV000318466 | likely benign | Cardiovascular phenotype | 2019-06-21 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Labcorp Genetics |
RCV000471101 | SCV000552094 | likely benign | RASopathy | 2024-01-31 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000151711 | SCV000920138 | likely benign | not specified | 2024-09-04 | criteria provided, single submitter | clinical testing | Variant summary: RAF1 c.935T>C (p.Val312Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251364 control chromosomes. The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAF1 causing Noonan Syndrome And Related Conditions phenotype (2.5e-05). c.935T>C has been reported in the literature in at-least one individual affected with Noonan Syndrome And Related Conditions (examples:Hakami_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26918529, 27974047). ClinVar contains an entry for this variant (Variation ID: 40612). Based on the evidence outlined above, the variant was classified as likely benign. |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV001256890 | SCV001433388 | uncertain significance | Hypertrophic cardiomyopathy 1 | 2019-12-30 | criteria provided, single submitter | clinical testing |